Construction comprising or consisting of a peptide sequence capable of inhibiting the interaction of filamin A with the UT receptor - pharmaceutical composition and associated products

Abstract

The present invention relates to a construct comprising a cell penetrating peptide sequence coupled by a peptide bond to at least one first binding molecule which is coupled by a peptide bond to the N-terminal end of an interfering amino acid sequence chosen from the following sequences: SEQ ID NO: 1 which forms domain 2104-2206 of the human FlnA protein and SEQ ID NO: 2 which defines domain 330-350 of the UT receptor, the sequences having at least 90% identity and, preferably, at least 95% identity with the abovementioned sequences and the sequences substantially homologous to the abovementioned sequences and preferably deriving from the latter by one or more conservative substitutions.

Description

Title of the invention: Construction comprising or consisting of a peptide sequence capable of inhibiting the interaction of filamin A with the UT receptor - pharmaceutical composition and associated products Technical field

[0001] The present invention relates to synthetic constructs containing peptide sequences, which are capable of penetrating into cells (passing the plasma membrane) and associating with the amino acid sequence of the C-terminal domain of the urotensin II (UII) receptor, namely the UT receptor or capable of penetrating into cells and associating with the amino acid sequence of the Filamin A domain involved in the interaction of Filamin A with the UT receptor.

[0002] These constructs can be used as a medicament or as a diagnostic agent, in particular for the treatment / diagnosis of cancer and more specifically the treatment of glioblastoma.

[0003] The present invention also relates to a pharmaceutical composition containing such constructs as well as other associated products. Technological background

[0004] The expression and involvement of Filamin A (FlnA) in the processes associated with tumorigenesis and tumor aggressiveness have already been widely described in the literature. Although its expression is not systematically increased, variations in FlnA expression are however associated with a poor prognosis and are correlated with tumor aggressiveness, and the metastatic process, in particular. Indeed, FlnA is overexpressed in breast cancers (see the publication “Inhibition of Filamin-A reduces cancer metastatic potential” by Jiang et al., 2012 published in International Journal of Biological Science and “Differential expression of filamin A and its clinical significance in breast cancer” by Tian et al., 2012 published in Oncology Letters), in lung adenocarcinomas (see the publication “A positive relationship between filamin and VEGF in patients with lung cancer” by Uramoto et al., 2010 published in Anticancer Research), in pancreatic cancers (see the publication “Targeting mechanoresponsive proteins in pancreatic cancer: 4-hydroxyacetophenone blocks dissemination and invasion by activating MYH14” by Surcel et al., 2018 published in Cancer Research) and in melanomas (see the publication “Filamin A expression correlates with proliferation and invasive properties ofhuman metastatic melanoma tumors: implications for survival in patients” by . Zhang et al., 2014 published in the Journal of Cancer Research and Clinical Oncology), showing the highest levels systematically associated with a poor prognosis in terms of survival, characterized by a higher number of metastases and earlier recurrence.

[0005] The decrease in the level of expression of FlnA could be observed in prostate cancer (see the publication “Filamin A regulates MMP-9 expression and suppresses prostate cancer cell migration and invasion” by Sun et al., 2014 published in Tumor Biology), in colorectal adenocarcinomas (see the publication “New cancer suppressor gene for colorectal adenocarcinoma: Filamin A” by Tian et al., 2015 published in World Journal of Gastroenterology) as well as in gastric, renal and nasopharyngeal carcinomas (see the publications “An antiproliferative gene FLNA regulates migration and invasion of gastric carcinoma cell in vitro and its clinical significance” by Sun et al., 2014 published in Tumor Biology; “Interactions between Filamin A and MMP-9 Regulate Proliferation and Invasion in Renal Cell Carcinoma” by Sun et al., 2014 published in the Asian Pacific Journal of Cancer Prevention and “Absent expression of FLNA is correlated with poor prognosis of nasopharyngeal cancer” published by Sun et al., 2014 in the journal Tumor Biology). In these cases, decreased expression of FlnA is very often associated with a poor prognosis.

[0006] Taken together, the effects of FlnA expression variations in tumors suggest that this protein plays a central role in regulating mechanisms associated with tumorigenesis. It appears to be a good diagnostic and prognostic marker, potentially useful in tumor management. Thus, the use of FlnA as a rapid diagnostic marker of treatment response and / or recurrence may also be a strategy for non-invasive monitoring of therapeutic response during patient management.

[0007] Diffuse gliomas in adults are the most common and aggressive primary brain tumors, particularly anaplastic gliomas (grade III) and glioblastomas (GB). The standard first-line treatment used to date is the Stupp protocol (see the publication "Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma" by Stupp et al., 2005 published in The New England Journal of Medicine), which is based on surgical resection of the tumor as complete as possible, followed by concomitant radio-chemotherapy, and adjuvant chemotherapy with temolozomide (TMZ). However, recurrence is almost inevitable and occurs within 7 to 10 months after diagnosis, which explains the median patient survival of 15 to 17 months. This is mainly due to the highly invasive diffuse nature of GB which does not allow complete resection of the tumor, pathological neoangiogenesis and resistance to treatments.

[0008] At relapse, no treatment can significantly improve patient survival and the use of chemotherapy is associated with response rates of approximately 5%. Although many different therapeutic strategies have been developed in recent years, unfortunately the many targeted therapies developed have not been effective in terms of overall patient survival. It should be noted, however, that anti-angiogenic therapies (Bevacizumab, Afilbercept, Sunitib and Cediranib), including Bevacizumab, an antibody directed against VEGF-A, allow a response rate of 30% at relapse, as well as an increase in progression-free survival and quality of life for patients with GB.

[0009] Thus, although some progress has been made in the management of diffuse high-grade gliomas or GB, recurrence remains the rule, and must therefore be treated.

[0010] Invasion of healthy brain parenchyma by GB cells, at the edge or at a distance from the resection zone, constitutes a major therapeutic challenge. These invasion mechanisms are driven by cellular transformations linked to environmental constraints such as hypoxia and angiogenesis, responsible for a mesenchymal transition (MT) mainly controlled by the transcription factors STAT3 and CEBPa which stimulate 70% of mesenchymal secondary genes. Hypoxia associated with TM notably leads to the overexpression of 7-transmembrane domain receptors coupled to G proteins (GPCRs) of chemokines. The most widely studied chemotactic GPCR in GB is CXCR4 relaying its pro-migratory effects via couplings and the Gai / PI3K / Akt and Gal2 / 13 / Rho / ROCK / Myosin pathways as well as its clathrin-dependent endocytosis and recycling relayed by the activity of [3-arrestins.Previously published work has also demonstrated that the UT receptor of the neuropeptide UII behaves like a chemokine receptor that can stimulate the directional migration of GB cells via the sequential activation of Gai / PI3K then Gal3 / Rho / ROCK allowing cell polarization, the emission of lamellipodia, the polymerization of actin stress fibers, and cell contraction (See the publication “Signaling switch of the urotensin II vasosactive peptide GPCR: prototypic chemotaxic mechanism in glioma” by Lecointre et al., published in 2015 in Oncogene and the thesis summary of Mr. Alexandre Mutel accessible via the following link: https: / / www.theses.fr / 2019NORMR081).

[0011] An object of the present invention is to provide constructs comprising or consisting of essentially peptide sequence(s) capable of penetrating into cells and interacting with the UT receptor of the human neuropeptide UII or the Fin A protein so as to inhibit the interaction between Fin A and the UT receptor.

[0012] Another object of the invention is to propose constructions such as those mentioned above which can be used as a drug or prognostic agent or diagnostic agent, in particular for cancer and more particularly for diffuse glioma, in particular in adults, anaplastic glioma (grade III) and more particularly glioblastoma.

[0013] Another aim of the invention is to propose constructions as mentioned above which make it possible to reduce or even prevent the invasion of healthy parenchyma relayed by the activation of the UT receptor, and other chemokine receptors following resection of a tumor of the diffuse glioma or glioblastoma type.

[0014] Another aim of the invention is to propose constructions as mentioned above which make it possible to counteract or limit resistance to current treatments for glioblastoma, namely in particular Temozolomide.

[0015] Another aim is to propose constructions which make it possible to obtain a synergy of action with anticancer drugs in other peripheral cancers, in particular tyrosine kinase inhibitors such as Gefitinib or DNA alkylating agents such as Temozolomide, in particular for the treatment of glioblastomas and lung, breast and prostate cancers.

[0016] Another aim of the present invention is to provide peptide sequences which make it possible to obtain the aforementioned constructions.

[0017] Brief summary of the invention

[0018] According to a first aspect, the present invention relates to a construct comprising a cell penetrating peptide sequence coupled by a peptide bond to at least one first binding molecule which is coupled by a peptide bond to the N-terminal end of an interfering amino acid sequence chosen from:

[0019] a) sequences comprising or consisting of the following sequence: VTYCPTEPGN YIINIKFADQHVPGSPFSVKVTGEGRVKESITRRRRAPSVANVGSHCDLSLKIPEI SIQD MTAQVTSPSG KTHEAEIVEGENHTYCIRFVPAE (SEQ ID NO: 1 or FlnA 2104-2206) which forms domain 2104-2206 of the human FlnA protein;

[0020] b) sequences comprising or consisting of a fragment of the sequence SEQ ID NO: 1 and capable of associating with the sequence VRGPGSGGGRGPVPSLQPRAR (SEQ ID NO: 2 or UT-330-350) which defines domain 330-350 of the UT receptor or with a fragment of this sequence SEQ ID NO: 2, in particular with the fragment of sequence GGGRGPVPSLQPRAR (SEQ ID NO: 3 or UT-336-350) forming domain 336-350 of the UT receptor or with the fragment RGPVPSLQPRAR (SEQ ID NO: 4 or UT-339-350) defining domain 339-350 of the UT receptor;

[0021] c) the sequences comprising or consisting of a fragment of the sequence SEQ ID NO: 2, in particular the fragment forming domain 330-350 of the UT receptor (SEQ ID NO: 2) or the fragment forming domain 336-350 of the UT receptor (SEQ ID NO: 3) or the fragment forming domain 339-350 of the UT receptor (SEQ ID NO: 4) and capable of associating with a fragment of the sequence SEQ ID NO: 1;

[0022] d) sequences having at least 90% identity and, preferably, at least 95% identity with the sequences defined in paragraphs a) to c); and a. sequences substantially homologous to the sequences defined in paragraphs a) to d) and preferably deriving from the latter by one or more conservative substitutions.

[0023] It is the inventors' merit to have shown that the above-mentioned constructs, some of which may be constructs, interfere with the Filamin A protein and the UII UT receptor and can thus be used as a drug. The above-mentioned constructs have in vitro activity on glioblastoma cells and prevent the spread of glioblastoma cancer cells after tumor resection.

[0024] According to a particular embodiment, the first binding molecule is an amino acid, optionally modified and in particular a beta-alanine molecule. The bond with the permeant sequence and the first binding molecule is a peptide bond and the bond between the first binding molecule and the interfering sequence is a peptide bond.

[0025] According to a particular embodiment, the interfering amino acid sequence is chosen from the amino acid sequences defined in paragraph b) and in particular from the following sequences:

[0026] - MTAQVTSPSGKTHEAEIVE (SEQ ID NO: 5 or FlnA-D20-CD), GNYIINIK- FADQHVPGSPFSVKVT (SEQ ID NO: 6 or FlnA-D19-FG), THEAEIVE-GENHTYCIRF (SEQ ID NO: 7 or FlnA-D20-DE), the peptide sequences having at least 90% and preferably at least 95% identity with said sequences and the substantially homologous peptide sequences, preferably deriving from the sequences SEQ ID NO: 5, SEQ ID NO: 6 or SEQ ID NO: 7 by one or more conservative substitutions.

[0027] - RGPVPSLQPRAR (SEQ ID NO: 4 or UT-339-350) and GGGRGPVPSLQPRAR (SEQ ID NO: 3 or UT-336-350) and the peptide sequences having at least 90% and preferably at least 95% identity with said sequences SEQ ID NO: 3 and SEQ ID NO: 4 and the substantially homologous peptides, preferably deriving from the sequences SEQ ID NO: 3 or SEQ ID NO: 4 by one or more conservative substitutions.

[0028] The cell penetration sequence is not limited according to the invention. Advantageously, the cell penetration sequence is chosen from the following sequences:

[0029] -TCTWLKYH (SEQ ID NO: 8 or Glio) and the peptide sequences having at least 90% and preferably at least 95% identity with said sequence SEQ ID NO : 8 and substantially homologous sequences, preferably derived from the sequence SEQ ID NO: 8 by one or more conservative substitutions;

[0030] - the peptide sequence GRRRQRRKKRKCCKRKKRRQRRRG (SEQ ID NO: 9 or CycloGlio) in which residues 12 and 13 (cysteine) are linked by a disulfide bridge and in which residues 2 to 10 and 15 to 23 are dextrorotatory (D) amino acids and the peptide sequences having at least 90% and preferably at least 95% identity with said sequence SEQ ID NO: 9 and the substantially homologous sequences, preferably deriving from the sequence SEQ ID NO: 9 by one or more conservative substitutions, the two ends of said penetration sequence each being linked by a peptide bond to a first linker molecule which is an amino acid, optionally modified, said linker molecule itself being linked by a peptide bond to an interfering sequence, the two interfering sequences being identical or different.

[0031] These two penetration sequences exhibit rapid cell penetration kinetics; constructs containing these sequences penetrate cells within 5 minutes of the start of in vitro incubation.

[0032] The cell penetration sequence SEQ ID NO: 8 makes it possible to reduce potential penetrations into other cell types, and therefore undesirable side effects, during administration to the patient.

[0033] The cell penetration sequence SEQ ID NO: 9 or CycloGlio is a U-shaped molecule due to the disulfide bridge which links the two cysteine ​​molecules. It allows the synthesis of hairpin-shaped molecules. The two interfering sequences each linked to one end of the penetration sequence may or may not be identical. They may be, for example, two identical or different fragments of FlnA or two identical or different fragments of the UT receptor. It follows that when one arm is linked either to FlnA or to the UT receptor, the other arm being free, it repels any molecule approaching FlnA or the UT receptor, respectively. There is therefore a double action of inhibition of the relationship between FlnA and the UT receptor: inhibition due to the linkage with the construct of the invention and inhibition due to a steric effect due to the U-shape of the construct of the invention.

[0034] Advantageously, said cell penetration sequence is chosen from the peptide sequence GRRRQRRKKRKCCKRKKRRQRRRG (SEQ ID NO: 9 or CycloGlio) in which residues 12 and 13 (cysteine) are linked by a disulfide bridge and in which residues 2 to 10 and 15 to 23 are dextrorotatory (D) amino acids and the peptide sequences having at least 90% and preferably at least 95% identity with said sequence SEQ ID NO: 9 and the substantially homologous sequences, preferably deriving from the sequence SEQ ID NO: 9 by one or more conservative substitutions, in that the first two molecules of bond are identical and in particular beta alanine molecules;

[0035] and one of the interfering sequences is chosen from the sequences defined in paragraphs a) and b) above, in particular from the following interfering sequences: MTAQVTSPSGKTHEAEIVE (SEQ ID NO: 5 or FlnA-D20-CD), GNYIINIKFAD-QHVPGSPFSVKVT (SEQ ID NO: 6 or FlnA-D19-FG), THEAEIVEGENHTYCIRF (SEQ ID NO: 7 or FlnA-D20-DE) and the peptide sequences having at least 90% and preferably at least 95% identity with said sequences and the substantially homologous sequences, preferably deriving from the sequences SEQ ID NO: 5, SEQ ID NO: 6 or SEQ ID NO: 7 by one or more conservative substitutions,while the other interfering sequence is chosen from the sequences defined in paragraph c) above 1 and in particular from the following interfering sequences: RGPVPSLQPRAR (SEQ ID NO: 4 or UT-339-350) and GGGRGPVPSLQPRAR (SEQ ID NO: 3 or UT-336-350) and the peptide sequences having at least 90% and preferably at least 95% identity with said sequences SEQ ID NO: 3 and SEQ ID NO: 4 and the substantially homologous sequences, preferably deriving from the sequences SEQ ID NO: 3 or SEQ ID NO: 4 by one or more conservative substitutions.

[0036] Furthermore, this penetration sequence SEQ ID NO: 9 allows endosomal release of the construction of the invention, allowing cytosolic incorporation greater than 90%, thereby potentiating the interfering effects of the interfering sequences.

[0037] Advantageously, when said cell penetration sequence is chosen from the peptide sequence GRRRQRRKKRKCCKRKKRRQRRRG (SEQ ID NO: 9 or CycloGlio) in which residues 12 and 13 (cysteine) are linked by a disulfide bridge and in which residues 2 to 10 and 15 to 23 are dextrorotatory (D) amino acids and the peptide sequences having at least 90% and preferably at least 95% identity with said sequence SEQ ID NO: 9 and the substantially homologous sequences, preferably deriving from the sequence SEQ ID NO: 9 by one or more conservative substitutions, the lysines in positions 11 and 14 of said cell penetration sequence are acetylated. This acetylation avoids any risk of peptide bonding with another sequence, since lysines still have a free amine function, they can still bond even when they are part of a peptide sequence.

[0038] The present invention also relates to an interfering construct chosen from the following sequence constructs:

[0039] TVKVSFPSGPVHQDAFKINIIYNGXGrrrqrrkkrKCCKrkkrrqrrrGXGNYIINIKFA DQHVPGSPFSVKVT(SEQ ID: 10, also referred to as FlnA-CPPD19-FG-CycloGlio) wherein residues 37 and 38 are linked by a disulfide bridge, X is in both positions an optionally modified amino acid and preferably beta-alanine in both positions and residues 27 to 35 and 40 to 48 are dextrorotatory (D) amino acids and in which the lysines in positions 36 and 39 are acetylated;

[0040] EVIEAEHTKGSPSTVQATMXGrrrqrrkkrKCCKrkkrrqrrrGXMTAQVTSPSGKTH EAEIVE (SEQ ID NO: 11; also referred to as FlnA-CPPD20-CD-CycloGlio) wherein residues 32 and 33 are linked by a disulfide bridge, X is an optionally modified amino acid and preferably beta-alanine in both positions and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids and wherein the lysines at positions 31 and 34 are acetylated;

[0041] FRIS YTHNEGEVIEAEHTXGrrrqrrkkrKCCKrkkrrqrrrGXTHEAEIVEGENHTYSI RF (SEQ ID NO: 12; also referred to as FlnA-CPPD20-DE-CycloGlio) wherein residues 31 and 32 are linked by a disulfide bridge, X is an optionally modified amino acid and preferably beta-alanine and residues 21 to 29 and 34 to 42 are dextrorotatory (D) amino acids; wherein the lysines at positions 30 and 33 are acetylated;

[0042] TCTWLKYHXGNYIINIKFADQHVPGSPFSVKVT (SEQ ID NO: 13; also referred to as FlnA-CPPD19-FG-Glio) wherein X is an optionally modified amino acid and preferably beta-alanine;

[0043] TCTWLKYHXMTAQVTSPSGKTHEAEIVE (SEQ ID NO: 14; also referred to as FlnA-CPPD20-CD-Glio) wherein X is an optionally modified amino acid and preferably beta-alanine;

[0044] TCTWLKYHXTHEAEIVEGENHTYCIRF (SEQ ID NO: 15; also referred to as FlnA-CPPD20-DE-Glio) wherein X is an optionally modified amino acid and preferably beta-alanine;

[0045] RARPQLSPVPGRGGGXGrrrqrrkkrKCCKrkkrrqrrrGXGGGRGPVPSLQPRAR (SEQ ID NO: 16, also referred to as UT-CPP336-350-CycloGlio) wherein residues 28 and 29 are linked by a disulfide bridge, X is an optionally modified amino acid and preferably beta-alanine in both positions and residues 18 to 26 and 31 to 39 are dextrorotatory (D) amino acids wherein the lysines in positions 27 and 30 are acetylated;

[0046] RARPQLSPVPGRXGrrrqrrkkrKCCKrkkrrqrrrGXRGPVPSLQPRAR SEQ ID NO: 17; also referred to as UT-CPP339-350-CycloGlio) wherein residues 25 and 26 are linked by a disulfide bridge, X is an optionally modified amino acid and preferably beta-alanine in both positions and residues 15 to 23 and 28 to 36 are dextrorotatory (D) amino acids and wherein the lysines in positions 24 and 27 are acetylated,

[0047] TCTWLKYHXGGGRGPVPSLQPRAR (SEQ ID NO: 18; also referred to as UT-CPP336-350-Glio) wherein X is an optionally modified amino acid and preferably beta-alanine;

[0048] - TCTWLKYHXRGPVPSLQPRAR (SEQ ID NO: 19; also referred to as UT- CPP339-350-Glio) in which X is an optionally modified amino acid and preferably beta-alanine;

[0049] - constructions exhibiting at least 90% identity and preferably at least 95% of identity with the aforementioned constructions; and

[0050] - the substantially homologous constructions and preferably deriving from the sequences SEQ ID NO: 10 to SEQ ID NO: 19 by one or more conservative substitutions.

[0051] The constructs of sequence SEQ ID NO: 19, SEQ ID NO: 11, SEQ ID NO: 18, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 13, SEQ ID NO: 17 prove to be particularly effective on several types of solid cancer (glioblastoma, prostate, lung and breast) with regard to cell penetration and inhibition of migration of cancer cells. The same is true for the marked constructs containing these sequences.

[0052] In particular, the present invention relates to the following sequence constructs: The present invention also relates to the following sequence constructs:

[0053] TVKVSFPSGPVHQDAFKINIIYNGAGrrrqrrkkrKCCKrkkrrqrrrGAGNYIINIKFA DQHVPGSPFSVKVT(SEQ ID: 28, also referred to as FlnA-CPPD19-FG-CycloGlio-syn) wherein residues 37 and 38 are disulfide bonded, alanines at positions 25 and 50 are beta-alanine and residues 27 to 35 and 40 to 48 are dextrorotatory (D) amino acids and wherein lysines at positions 36 and 39 are acetylated;

[0054] EVIEAEHTKGSPSTVQATMAGrrrqrrkkrKCCKrkkrrqrrrGAMTAQVTSPSGKTH EAEIVE (SEQ ID NO: 29; also referred to as FlnA-CPPD20-CD-CycloGlio-syn) wherein residues 32 and 33 are disulfide bonded, alanines at positions 20 and 45 are beta-alanine, and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids; and wherein lysines at positions 31 and 34 are acetylated;

[0055] FRISYTHNEGEVIEAEHTAGrrrqrrkkrKCCKrkkrrqrrrGATHEAEIVEGENHTYSI RF (SEQ ID NO: 30; also referred to as FlnA-CPPD20-DE-CycloGlio-syn) wherein residues 31 and 32 are disulfide bonded, alanines at positions 19 and 44 are beta-alanine, and residues 21 to 29 and 34 to 42 are dextrorotatory (D) amino acids;

[0056] TCTWLKYHAGNYIINIKFADQHVPGSPFSVKVT (SEQ ID NO: 31; also referred to as FlnA-CPPD19-FG-Glio-syn) wherein the alanine at position 9 is a beta-alanine) and wherein the lysines at positions 30 and 33 are acetylated;

[0057] TCTWLKYHAMTAQVTSPSGKTHEAEIVE (SEQ ID NO: 32; also called FlnA-CPPD20-CD-Glio-syn) in which the alanine at position 9 is a beta-alanine;

[0058] TCTWLKYHATHEAEIVEGENHTYCIRF (SEQ ID NO: 33; also referred to as FlnA-CPPD20-DE-Glio-syn) wherein the alanine at position 9 is a beta-alanine;

[0059] RARPQLSPVPGRGGGAGrrrqrrkkrKCCKrkkrrqrrrGAGGGRGPVPSLQPRAR (SEQ ID NO: 34; also referred to as UT-CPP336-350-CycloGlio-syn) wherein residues 28 and 29 are disulfide bonded, alanines at positions 16 and 41 are beta-alanine and residues 18 to 26 and 31 to 39 are dextrorotatory (D) amino acids and wherein lysines at positions 27 and 30 are acetylated;

[0060] RARPQLSPVPGRAGrrrqrrkkrKCCKrkkrrqrrrGARGPVPSLQPRAR (SEQ ID NO: 35; also referred to as UT-CPP339-350-CycloGlio-syn) wherein residues 25 and 26 are disulfide bonded, alanines at positions 13 and 38 are beta-alanines and residues 15 to 23 and 28 to 36 are dextrorotatory (D) amino acids and wherein lysines at positions 24 and 27 are acetylated;

[0061] TCTWLKYHAGGGRGPVPSLQPRAR (SEQ ID NO: 36; also referred to as UT-CPP336-350-Glio-syn) wherein the alanine at position 9 is a beta-alanine;

[0062] - TCTWLKYHARGPVPSLQPRAR (SEQ ID NO: 37; also referred to as UT- CPP339-350-Glio-syn) in which the alanine at position 9 is a beta-alanine;

[0063] the sequences having at least 90% identity and, preferably, at least 95% identity with the abovementioned sequences and the sequences substantially homologous to the abovementioned sequences and preferably deriving from the latter by one or more conservative substitutions.

[0064] When the constructs comprise the Cycloglio sequence (SEQ ID NO: 9) or a sequence identical to 90% or 95% of this sequence or a substantially homologous sequence and preferably deriving from this sequence by one or more conservative substitutions, the lysines located on either side of the disulfide bridge are preferably acetylated, i.e. linked to a CH3CO radical, when they are not linked to a molecule of a labeling agent.

[0065] The construct of sequence SEQ ID NO: 35 or UT-339-350-CycloGlio provides effects that are systematically found in various glioblastoma cell lines. This interfering and penetrating construct (peptide) inhibits the motility of glioblastoma cells, the chemotactic migration in response to UII of glioblastoma cells, reduces the viability of glioblastoma cells when applied alone or in combination with TMZ (Temozolomide) chemotherapy, reduces the viability and promotes the effects of chemotherapy with Gefitinib on a lung cancer cell line.

[0066] The constructs of sequence SEQ ID NO: 37, SEQ ID NO: 47, SEQ ID NO: 29, SEQ ID NO: 39, SEQ ID NO: 36, SEQ ID NO: 46, SEQ ID NO: 32, SEQ ID NO: 42, SEQ ID NO: 33, SEQ ID NO: 43, SEQ ID NO: 31, SEQ ID NO: 41, SEQ ID NO: 35 and SEQ ID: 45 are particularly effective on several types of solid cancer (glioblastoma, prostate, lung and breast) with regard to cell penetration and inhibition of cancer cell migration.

[0067] The present invention also relates to constructs as mentioned above which further comprise a labeling agent capable of penetrating into the cell. In particular, the penetration sequence is linked to at least one labeling agent. The labeling agent may be a fluorophore.

[0068] The labeling agent is preferably a particular permeant fluorophore, 5-carboxytetramethylrhodamine or 7-diethylaminocoumarin-3-carboxylic acid.

[0069] Advantageously, when the penetration sequence is chosen from the peptide sequence GRRRQRRKKRKCCKRKKRRQRRRG (SEQ ID NO: 9 or CycloGlio) in which residues 12 and 13 (cysteine) are linked by a disulfide bridge and in which residues 2 to 10 and 15 to 23 are dextrorotatory (D) amino acids and the peptide sequences having at least 90% and preferably at least 95% identity with said sequence SEQ ID NO: 9 and the substantially homologous sequences, preferably deriving from the sequence SEQ ID NO: 9 by one or more conservative substitutions, a molecule of said labeling agent is linked to the lysines in position 11 and 14 and said labeling agent is in particular and preferably 5-carboxytetramethylrhodamine.

[0070] Thus, the present invention also relates to a construct which comprises or consists of a peptide sequence chosen from the sequences SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, the constructs having at least 90% identity and preferably at least 95% identity with the abovementioned constructs and the constructs which are substantially homologous and preferably derived from the abovementioned sequences by one or more conservative substitutions in which the first residue of the permeant sequence is linked by a peptide bond to the carboxylic acid function of beta alanine which is linked by a peptide bond with the carboxyl group of 7-diethylaminocoumarin-3-carboxylic acid.

[0071] The present invention also relates to a construct which comprises or consists of a peptide sequence chosen from the sequences SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 17, the constructs having at least 90% identity and preferably at least 95% identity with the abovementioned constructs and the constructs which are substantially homologous and preferably derived from the abovementioned sequences by one or more conservative substitutions in which residues 11 and 14 (K: lysine) of the sequence permeant are each linked by a peptide bond with the carboxylic acid group of 5-carboxytetramethylrhodamine.

[0072] Thus, the present invention also relates to the following sequences, which can be used for the treatment and diagnosis / prognosis of the pathologies mentioned below:

[0073] TVKVSFPSGPVHQDAFKINIIYNGAGrrrqrrkkrKCCKrkkrrqrrrGAGNYIINIKFA DQHVPGSPFSVKVT(SEQ ID: 38, also referred to as Mq-FlnA-CPPD19-FG-CycloGlio-syn) wherein residues 37 and 38 are linked by a disulfide bridge, the alanines at positions 25 and 50 are beta-alanine and residues 27 to 35 and 40 to 48 are dextrorotatory (D) amino acids and residues 36 and 39 are each linked by a peptide bond to the carboxylic acid group of 5-carboxytetramethylrhodamine;

[0074] EVIEAEHTKGSPSTVQATMAGrrrqrrkkrKCCKrkkrrqrrrGAMTAQVTSPSGKTH EAEIVE (SEQ ID NO: 39; also referred to as Mq-FlnA-CPPD20-CD-CycloGlio-syn) wherein residues 32 and 33 are linked by a disulfide bridge, the alanines at positions 20 and 45 are beta-alanine and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids and residues 31 and 34 are each linked by a peptide bond to the carboxylic acid group of 5-carboxytetramethylrhodamine;

[0075] FRISYTHNEGEVIEAEHTAGrrrqrrkkrKCCKrkkrrqrrrGATHEAEIVEGENHTYSI RF (SEQ ID NO: 40; also referred to as Mq-FlnA-CPPD20-DE-CycloGlio-syn) wherein residues 31 and 32 are linked by a disulfide bridge, the alanines at positions 19 and 44 are beta-alanine and residues 21 to 29 and 34 to 42 are dextrorotatory (D) amino acids and residues 30 and 33 are each linked by a peptide bond to the carboxylic acid group of 5-carboxytetramethylrhodamine;

[0076] ATCTWLKYHAGNYIINIKFADQHVPGSPFSVKVT (SEQ ID NO: 41; also referred to as Mq-FlnA-CPPD19-FG-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid;

[0077] ATCTWLKYHAMTAQVTSPSGKTHEAEIVE (SEQ ID NO: 42; also referred to as Mq-FlnA-CPPD20-CD-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid;

[0078] ATCTWLKYHATHEAEIVEGENHTYCIRF (SEQ ID NO: 43; also referred to as Mq-FlnA-CPPD20-DE-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid;

[0079] RARPQLSPVPGRGGGAGrrrqrrkkrKCCKrkkrrqrrrGAGGGRGPVPSLQPRAR (SEQ ID NO: 44; also referred to as Mq-UT-CPP336-350-CycloGlio-syn) wherein residues 28 and 29 are linked by a disulfide bridge, the alanines at positions 16 and 41 are beta-alanine and residues 18 to 26 and 31 to 39 are dextrorotatory (D) amino acids and residues 27 and 30 are each linked by a peptide bond to the carboxylic acid group of tetramethylrhodamine;

[0080] RARPQLSPVPGRAGrrrqrrkkrKCCKrkkrrqrrrGARGPVPSLQPRAR SEQ ID NO: 45; also referred to as Mq-UT-CPP339-350-CycloGlio-syn) wherein residues 25 and 26 are linked by a disulfide bridge, the alanines at positions 13 and 38 are beta-alanine and residues 15 to 23 and 28 to 36 are dextrorotatory (D) amino acids residues 24 and 27 are each linked by a peptide bond to the carboxylic acid group of tetramethylrhodamine,

[0081] ATCTWLKYHAGGGRGPVPSLQPRAR (SEQ ID NO: 46; also referred to as Mq-UT-CPP336-350-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid;

[0082] ATCTWLKYHARGPVPSLQPRAR (SEQ ID NO: 47; also referred to as Mq-UT-CPP339-350-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid;

[0083] -the sequences having at least 90% identity and, preferably, at least 95% identity with the aforementioned sequences; and

[0084] the sequences substantially homologous to the abovementioned sequences and preferably deriving from the latter by one or more conservative substitutions.

[0085] The present invention also relates to a construct according to the invention for its use as a medicament or diagnostic / prognostic agent, in particular for cancer, in particular solid cancerous tumors, breast cancer, lung cancer more particularly in the treatment of pulmonary adenocarcinomas, melanomas, prostate cancer, colon cancer in particular colorectal adenocarcinomas, stomach cancer, in particular gastric carcinomas, kidney cancer, in particular renal carcinomas, nasopharyngeal cancers in particular nasopharyngeal carcinomas, pancreatic cancer, diffuse glioma and glioblastoma in a patient, in particular a human.

[0086] The present invention also relates to a pharmaceutical composition which comprises, as active ingredient, at least one construction according to the invention and a solvent, excipient and / or vehicle.

[0087] The composition of the invention may be in the form of a solid, in particular a powder, a gel or an injectable solution, possibly colloidal.

[0088] The composition can be taken orally, injected intravenously or administered intranasally after resection of the tumor, partly in the case of glioblastomas, concomitantly or at a time after the injection of a chemotherapy product.

[0089] When the pharmaceutical composition of the invention is in the form of a liquid, gel, or solid, it can be introduced into the space created by the resection of the tumor, in particular in the case of blastomas and glioblastomas, before the patient is treated with chemotherapy. The constructs and peptides of the invention will then penetrate into the surrounding cells and block the invasion of the glioblastoma.

[0090] The composition of the invention can also be injected into a tumor.

[0091] The present invention also relates to a nucleic acid coding for one of the sequences corresponding to the sequences according to the invention, in particular for a construction chosen from the following sequences: SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7.

[0092] The present invention also relates to a vector comprising such a nucleic acid, preferably an adenoviral or lentiviral vector.

[0093] The present invention also relates to a combination product containing at least one construct according to the invention and in particular a construct chosen from the constructs of sequence SEQ: ID NO: 16, SEQ ID NO: 34, SEQ ID NO: 17, SEQ ID NO: 35, SEQ ID NO: 10, SEQ ID NO: 28, SEQ ID NO: 11, SEQ ID NO: 29, SEQ ID NO: 12, SEQ ID NO: 30, SEQ ID NO: 18, SEQ ID NO: 36, SEQ ID NO: 19, SEQ ID NO: 37, SEQ ID NO: 13, SEQ ID NO: 31, SEQ ID NO: 14, SEQ ID NO: 32, SEQ ID NO: 15, SEQ ID NO: 33 and an anticancer agent chosen in particular from tyrosine kinase inhibitors, in particular Gefitinib and alkylating agents causing DNA double-strand breaks and cell death, in particular Temozolomide for their simultaneous, delayed or sequenced use.

[0094] The present invention also discloses the following sequences which are used for comparison:

[0095] ALQQSRLPPQVSPQDGALAAGrrrqrrkkrKCCKrkkrrqrrrGAALAGDQPSVQPPL RSQQLA (SEQ ID NO: 20 or FlnA-Hla-Cycloglio) in which residues 32 and 33 are linked by a disulfide bridge, the alanine at position 20 and position 45 is a beta alanine (in both positions) and residues 22 to 30 and 35 to 43 are acids dextrorotatory amines (D);

[0096] WTQQGGQAYTYQPALQQSRAGrrrqrrkkrKCCKrkkrrqrrrGARSQQLAPQYTYA QGGQQTW (SEQ ID NO: 21 or FlnA-Hlb-Cycloglio) wherein residues 32 and 33 are linked by a disulfide bridge, the alanine at positions 20 and 45 is a beta alanine (in both positions) and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids;

[0097] AKTLSDVFVSSTEHLSHNSAGrrrqrrkkrKCCKrkkrrqrrrGASNHSLHETSSVFVD SLTKA (SEQ ID NO: 22 or FlnA-H2a-CycloGlio) wherein residues 32 and 33 are linked by a disulfide bridge, the alanine at position 20 and that at position 45 is a beta alanine (in both positions) and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids;

[0098] PGPGPAGHQPASTAKTLSDAGrrrqrrkkrKCCKrkkrrqrrrGADSLTKATSAPQHG APGPGP (SEQ ID NO: 23 or FlnA-H2b-CycloGlio) wherein residues 32 and 33 are linked by a disulfide bridge, the alanine at position 20 and that at position 45 is a beta alanine and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids;

[0099] TCTWLKYHAALAGDQPSVQPPLRSQQLA (SEQ ID NO: 24 or FlnA-Hla-Glio) wherein the alanine at position 9 is a beta-alanine.

[0100] TCTWLKYHARSQQLAPQYTYAQGGQQTW (SEQ ID NO: 25 or FlnA-Hlb-Glio) wherein the alanine at position 9 is a beta-alanine.

[0101] TCTWLKYHASNHSLHETSSVFVDSLTKA (SEQ ID NO: 26 or FlnA-H2a-Glio) wherein the alanine at position 9 is a beta-alanine.

[0102] TCTWLKYHADSLTKATCAPQHGAPGPGP (SEQ ID NO: 27 or FlnA-H2b-Glio) wherein the alanine at position 9 is a beta-alanine.

[0103] The present invention discloses, for comparison, the following constructs: ALQQSRLPPQVSPQDGALAAGrrrqrrkkrKCCKrkkrrqrrrGAALAGDQPSVQPPLRS QQLA (SEQ ID NO: 48 or Mq-FlnA-Hla-Cycloglio-syn) in which residues 32 and 33 are linked by a disulfide bridge, the alanines at positions 20 and 45 are beta-alanine and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids and residues 31 and 34 are each linked by a peptide bond to the carboxylic acid group of 5-carboxytetramethylrhodamine,

[0104] WTQQGGQAYTYQPALQQSRAGrrrqrrkkrKCCKrkkrrqrrrGARSQQLAPQYTYA QGGQQTW (SEQ ID NO: 49 or Mq-FlnA-Hlb-Cycloglio-syn) wherein residues 32 and 33 are linked by a disulfide bridge, the alanines at positions 20 and 45 are beta-alanine and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids and residues 31 and 34 are each linked by a peptide bond to the carboxylic acid group of 5-carboxytetramethylrhodamine;

[0105] AKTLSDVFVSSTEHLSHNSAGrrrqrrkkrKCCKrkkrrqrrrGASNHSLHETSSVFVD SLTKA (SEQ ID NO: 50 or Mq-FlnA-H2a-CycloGlio-syn) in which the residues 32 and 33 are linked by a disulfide bridge, the alanines at positions 20 and 45 are beta-alanine and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids and residues 31 and 34 are each linked by a peptide bond to the carboxylic acid group of 5-carboxytetramethylrhodamine;

[0106] PGPGPAGHQPASTAKTLSDAGrrrqrrkkrKCCKrkkrrqrrrGADSLTKATSAPQHG APGPGP (SEQ ID NO: 51 or Mq-FlnA-H2b-CycloGlio-syn) wherein residues 32 and 33 are linked by a disulfide bridge, the alanines at positions 20 and 45 are beta-alanine and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids and residues 31 and 34 are each linked by a peptide bond to the carboxylic acid group of 5-carboxytetramethylrhodamine;

[0107] ATCTWLKYHAALAGDQPSVQPPLRSQQLA (SEQ ID NO: 52 or Mq-FlnA-Hla-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid;

[0108] ATCTWLKYHARSQQLAPQYTYAQGGQQTW (SEQ ID NO: 53 or Mq-FlnA-Hlb-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid;

[0109] ATCTWLKYHASNHSLHETSSVFVDSLTKA (SEQ ID NO: 54 or Mq-FlnA-H2a-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid;

[0110] ATCTWLKYHADSLTKATCAPQHGAPGPGP (SEQ ID NO: 55 or Mq-FlnA-H2b-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid. [YES] Definitions

[0112] The term “patient” refers throughout the present application to a mammal, male or female, adult or not (child) and particularly to a human.

[0113] The term "treatment" includes curative and preventive treatment. Curative treatment consists of at least one of the following: alleviating, improving and / or eliminating, reducing or stabilizing at least one symptom as well as delaying the progression or onset of a symptom of an impaired health condition. Preventive treatment consists of at least one of the following: avoiding the deterioration of the health condition health, reduce the risk of the onset of an impaired health condition, reduce the incidence, development and delay the onset of at least one symptom of an impaired health condition.

[0114] The term "penetrating sequence" designates a peptide or peptide sequence capable of transferring into a cell without causing substantial damage to the latter's membrane and capable of being used as a vector for other molecules to which it is bound.

[0115] The terms "interfering sequence" designate a peptide sequence capable of binding to a given peptide sequence possibly forming part of a protein and thus capable of modifying the mechanisms in which the given peptide sequence or the protein of which the latter forms part is involved.

[0116] The terms “sequence derived from” designate a peptide sequence longer than the sequence from which it is derived or a sequence homologous to the sequence from which it is derived.

[0117] The term "percentage identity" refers to the number of identical residues in two sequences to be compared, obtained after the best alignment, this percentage being purely statistical and the differences between the two sequences being distributed randomly and over their entire length. By "best alignment" or "optimal alignment" is meant the alignment for which the percentage identity determined as below is the highest. Sequence comparisons between two are traditionally carried out by comparing these sequences after having aligned them optimally, said comparison being carried out by segment or by "comparison window" to identify and compare local regions of sequence similarity. For example, the BLOSUM matrices and the local homology algorithm of Smith and Waterman (1981, J. Mol Evol., 18:38-46) can be used. Any other known method can also be used.

[0118] The term "conservative substitution" refers to the change of one amino acid for another without altering the overall conformation of the peptide and without altering the function of the peptide. Amino acids with similar properties are well known. For example, arginine, histidine, and lysine are hydrophilic and basic amino acids that are interchangeable. Isoleucine can be replaced by leucine, methionine, or valine. Asparagine, glutamine, serine, and threonine can be interchangeable.

[0119] The terms “essentially peptide” mean that more than 50% of the bonds connecting amino acids are peptide bonds but that certain residues may be linked to molecules other than amino acids or to amino acids but for example by a disulfide bridge.

[0120] The acronym GB stands for glioblastoma. Figures

[0121] [Fig.l] schematically represents the mechanism of interaction between filamin A and the UT receptor

[0122] [Fig.2] schematically represents the mechanism of inhibition of the interaction between filamin A and the UT receptor provided by the constructs of the invention of the UT-CPP336-350-Cycloglio family (namely the constructs corresponding to the sequences SEQ ID NO: 16, SEQ ID NO: 34 and SEQ ID NO: 44;

[0123] [Fig. 3] schematically represents the mechanism of inhibition of the interaction between filamin A and the UT receptor provided by the constructs of the invention of the UT-CPP339-350-Cycloglio family (namely the constructs corresponding to the sequences SEQ ID NO: 17, SEQ ID NO: 35 and SEQ ID NO: 45;

[0124] [Fig.4] schematically represents the mechanism of inhibition of the interaction between filamin A and the UT receptor provided by the constructs of the invention of the FlnA-CPPD19-FG-Cycloglio- family (namely the constructs corresponding to the sequences SEQ ID NO: 10, SEQ ID NO: 28 and SEQ ID NO: 38;

[0125] [Fig.5] schematically represents the mechanism of inhibition of the interaction between filamin A and the UT receptor provided by the constructs of the invention of the FlnA-CPPD20-CD-Cycloglio- family (namely the constructs corresponding to the sequences SEQ ID NO: 11, SEQ ID NO: 29 and SEQ ID NO: 39;

[0126] [Fig.6] schematically represents the mechanism of inhibition of the interaction between filamin A and the UT receptor provided by the constructs of the invention of the FlnA-CPPD20-DE-Cycloglio- family (namely the constructs corresponding to the sequences SEQ ID NO: 12, SEQ ID NO: 30 and SEQ ID NO: 40;

[0127] [Fig.7] schematically represents the mechanism of inhibition of the interaction between filamin A and the UT receptor provided by the constructs of the invention of the UTCPP339-350-Glio- family (namely the constructs corresponding to the sequences SEQ ID NO: 19, SEQ ID NO: 37 and SEQ ID NO: 47;

[0128] [Fig.8] schematically represents the mechanism of inhibition of the interaction between filamin A and the UT receptor provided by the constructs of the invention of the UTCPP336-350-Glio- family (namely the constructs corresponding to the sequences SEQ ID NO: 18, SEQ ID NO: 36 and SEQ ID NO: 46;

[0129] [Fig.9] schematically represents the mechanism of inhibition of the interaction between filamin A and the UT receptor provided by the constructs of the invention of the FlnACPP-D19-FG-Glio- family (namely the constructs corresponding to the sequences SEQ ID NO: 13, SEQ ID NO: 31 and SEQ ID NO: 41;

[0130] [Fig. 10] schematically represents the mechanism of inhibition of the interaction between filamin A and the UT receptor provided by the constructs of the invention of the FlnACPP-D20-CD-Glio- family (namely the constructs corresponding to the sequences SEQ ID NO: 14, SEQ ID NO: 32 and SEQ ID NO: 42;

[0131] [Fig. 11] schematically represents the mechanism of inhibition of the interaction between filamin A and the UT receptor provided by the constructs of the invention of the FlnACPP-D20-DE-Glio- family (namely the constructs corresponding to the sequences SEQ ID NO: 15, SEQ ID NO: 33 and SEQ ID NO: 43; Description of the examples of embodiment

[0132] Summaries of the constructions according to the invention as well as of the constructions serving as comparison.

[0133] The syntheses of the compounds corresponding to the following sequences: SEQ ID NO: 9, SEQ ID NO: 28, SEQ ID NO: 38, SEQ ID NO: 29, SEQ ID NO: 39, SEQ ID NO: 30, SEQ ID NO: 40, SEQ ID NO: 34, SEQ ID NO: 44, SEQ ID NO: 35, SEQ ID NO: 45, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50 and SEQ ID NO: 51 are carried out on 2-chlorotrityl chloride resin using a Symphony-X automated synthesizer (Gyros Protein Technologies) according to the Fmoc strategy. Briefly, the C-terminal amino acid of each sequence is anchored on 2-chlorotrityl resin to achieve a substitution rate of approximately 0.25 mmol / g in the presence of diisopropylethylamine in dichloromethane. Subsequently, the excess reactive sites are quenched by treatment with methanol in the presence of diisopropylethylamine.These resins are used for automated synthesis according to the protocols recommended by the Symphony-X manufacturer. For each synthesis cycle, deprotections are performed using 20% ​​piperidine in dimethylformamide (DMF) for 2 treatments of 5 minutes. After washing the resin with DMF (4x), couplings are performed by treating with a mixture of the amino acid Fmoc (5 eq), HAUT (5 eq), pure oxyma (5 eq) and diisopropylethylamine (15 eq) for 1 hour. Finally, the resin is washed with DMF (4x). The last two amino acids of the sequences that are coupled were Fmoc-Lys(Dde)-OH and Boc-Cys(Trt)-OH. Thus, the Dde protecting group is cleaved while keeping the peptides on resin by treatment 3x2 minutes with 2% hydrazine in DMF. The desired carboxy tetramethylrhodamine is optionally coupled to the side chains of the N-terminal lysines.Monomeric peptides are cleaved by TFA / water / TIPS / EDT (92.5%, 2.5%, 2.5%, 2.5%) treatment for 5 hours and precipitated in ether. Once centrifuged and decanted, the peptides are dissolved in water and purified by reverse-phase preparative HPLC. Pure monomeric peptides are dissolved in 50 mmol ammonium bicarbonate buffered to pH 10 with dilute ammonium hydroxide. They are stirred overnight in the presence of atmospheric oxygen to provide the desired symmetrical dimers. The solutions are finally lyo- . dried.

[0134] The syntheses of the compounds corresponding to the following sequences: SEQ ID NO: 8, SEQ ID NO: 31, SEQ ID NO: 41, SEQ ID NO: 32, SEQ ID NO: 42, SEQ ID NO: 33, SEQ ID NO: 43, SEQ ID NO: 36, SEQ ID NO: 46 and SEQ ID NO: 37, SEQ ID NO: 47, SEQ ID NO: 24, SEQ ID NO: 52, SEQ ID NO: 25 and SEQ ID NO: 53, SEQ ID NO: 26, SEQ ID NO: 54, SEQ ID NO: 27 and SEQ ID NO: 55, are carried out on 2-chlorotrityl chloride resin using a Symphony-X automated synthesizer (Gyros Protein Technologies) according to the Fmoc strategy. Briefly, the C-terminal amino acid of each sequence was anchored on 2-chlorotrityl resin to achieve a substitution rate of approximately 0.25 mmol / g in the presence of diisopropylethylamine in dichloromethane. Subsequently, the excess reactive sites were quenched by treatment with methanol in the presence of diisopropylethylamine.These resins are used for automated synthesis according to the protocols recommended by the Symphony-X manufacturer. For each synthesis cycle, deprotections were performed using 20% ​​piperidine in dimethylformamide (DMF) for 2 treatments of 5 minutes. After washing the resin with DMF (4x), couplings are performed by treating with a mixture of the amino acid Fmoc (5 eq), HAUT (5 eq), pure oxyma (5 eq) and diisopropylethylamine (15 eq) for 1 hour. Finally, the resin was washed with DMF (4x). The last coupled acid is DEAC if necessary. The peptides are cleaved by treatment with TFA / water / TIPS / EDT (92.5%, 2.5%, 2.5%, 2.5%) for 3 hours and precipitated in ether. Once centrifuged and decanted, the peptides are dissolved in water and purified by reverse-phase preparative HPLC.

[0135] In the same way it is possible to synthesize a construct of the cycloglio family which comprises two different interfering sequences, one being capable of binding to the UT receptor and the other to FlnA.

[0136] In vitro biological effects of the constructs of the invention:

[0137] Example 1: Study of the incorporation of the construct SEQ ID NO: 35 mimicking a sequence of the UT binding FlnA in the lines 8MG of glioblastoma, A549 of lung cancer, MDA-MB-231 of breast cancer and LnCAP of prostate cancer.

[0138] At tO 100,000 cells of each line are seeded in the wells of a 12-well plate previously coated with fibronectin (2 μg / ml; 1 h; 37°C). After 24 h of adhesion, the cells are treated with 100 nM of the construct SEQ ID NO: 35 which carries 5-carboxytetramethylrhodamine groups grafted onto the K2 residues (construct of sequence SEQ ID NO: 35) which make it possible to follow the incorporation of the peptide by video microscopy during 12 h of acquisition.

[0139] Table 1 groups together the results relating to the penetration kinetics of the construct SEQ ID NO 35 in the 8MG glioblastoma, A549 lung cancer, MDA-MB-231 breast cancer and LnCAP prostate cancer lines.

[0140] [Tables 1] Cancer Lineage Start of cytosolic penetration (min) Vesicular penetration (min) Diffusion throughout the cytosol (min) Glioblastoma 8MG <3 359.4 + 34.8 303.0 + 60.0 Lung A549 <3 249.3 + 32.17 416.3 + 53.84 Breast MDA-MB-231 <3 171 + 14.9 322.1 + 34.3 Prostate LnCAP <3 135.9 + 13.42 343.0 + 55.8

[0141] The construct of sequence SEQ ID NO: 35 mimicking a sequence of the UT binding FlnA rapidly penetrates into the 8MG glioblastoma, A549 lung cancer, MDA-MB-231 breast cancer and LnCAP prostate cancer lines with a first penetration time of less than 3 min. In addition, this construct of sequence SEQ ID NO: 35 diffuses completely into the cytosol of the solid cancer cells tested with very similar kinetics between 303 min and 416.3 min, thus the construct of sequence SEQ ID NO: 35 rapidly penetrates into the subcellular compartment in which FlnA and UT interact and can in fact relay its interfering effects rapidly after administration. In addition, the construct of sequence SEQ ID NO: 35 persists in the cytosol of all solid cancer lines at least 774 min after treatment, allowing the interfering properties of this construct to be maintained over time.

[0142] Example 2: Effect of the construct of the invention mimicking a segment of UT involved in binding to FlnA (SEQ ID NO: 35) on cell migration of GB lines 8MG, 42MG, U87 and GL15, A549 lung cancer, MDA-MB-231 breast cancer and LnCAP prostate cancer in response to 109 M of UII peptide.

[0143] At tO 30,000 GB 8MG, 42MG, U87 and GL15 cells and 75,000 A549 lung cancer cells, 100,000 MDA-MB-231 breast cancer cells and 75,000 LnCAP prostate cancer cells were seeded on the porous membrane (8 μm) of the upper Boyden chamber in the presence of 100 nM of the construct of sequence SEQ ID NO: 35. A homogeneous concentration of UII 109 M is placed in the lower chambers. After 24 hours, the cells of the upper chamber are removed and those of the lower chamber are fixed and with DAPI (4',6-diamino-2-phenylindole) then the membranes are cut and mounted between slide and coverslip and 8 microphotographs are taken per membrane. The number of cells / field semi-automatically using the ImageJ image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results (Statistical test: Two-way ANOVA; Sidak post-test, 2 membranes per condition and n=8 fields per membrane) are grouped in the following Table 2.

[0144] [Tables2] Line UII chemoattraction alone (% of control ± SEM) p-value UII chemoattraction in combination (% of control + SEM) Peptide inhibitory effect (%) p-value Glioblastom e 8MG 155.78 + 13.75 0.0036 98.30 + 17.97 -57.47 0.0028 42MG 160.81 + 7.55 0.0001 91.52 + 8.90 -69.3 0.0001 U87 154.11 + 6.98 0.0001 92.00 + 7.23 -62.11 0.0001 GL15 166.07 + 7.22 0.0001 72.93 + 8.12 -93.13 0.0001 Pulmonary A549 99.15 + 13.19 0.955 110.17 + 13.00 11.03 0.0109 Breast MDA-MB-2 31 70.13 + 7.12 0.0001 51.39 + 5.71 -18.74 0.0001 Prostatic LnCAP 240.02 + 25.13 0.0001 86.56 + 7.55 -153.46 0.0001

[0145] The construct of sequence SEQ ID NO: 35 completely and significantly prevents directional migration evoked by 109 M of UII in the GB and LnCAP prostate cancer lines 8MG, 42MG, U87 and GL15, with responses to UII in control condition ranging from -57.47%, p = 0.0028; -69.30%, p < 0.0001; -62.11%, p < 0.0001; -93.13%, p < 0.0001 to -153.46%, p < 0.0001, of migration stimulation, respectively. The construct of sequence SEQ ID NO: 35 is indeed an effective compound that can inhibit the directional migration of solid cancer lines responding to chemoattractant gradients of UII peptide.

[0146] Example 3: Effect of the construct of the invention mimicking a segment of UT involved in binding to FlnA (SEQ ID NO: 35) on cell migration of GB lines 8MG, 42MG, U87 and GL15, A549 lung cancer, MDA-MB-231 breast cancer and LnCAP prostate cancer in response to 50 ng / ml of EGF (Epidermal Growth Factor).

[0147] At T0, 30,000 8MG, 42MG, U87 and GL15 cells and 75,000 A549 lung cancer cells, 100,000 MDA-MB-231 breast cancer cells and 75,000 LnCAP prostate cancer cells were seeded on the porous membrane (8 μm) of the upper Boyden chamber in the presence of 100 nM of the construct of sequence SEQ ID NO: 35. A homogeneous concentration of EGF 50 ng / ml is placed in the lower chambers. After 24 h, the cells of the upper chamber are eliminated, and those of the lower chamber are fixed and the nuclei labeled with DAPI (4',6-diamino-2-phenylindole), then the membranes are cut and mounted between slide and coverslip and eight microphotographs are taken per membrane. The number of cells / field was quantified semi-automatically using ImageJ image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are summarized in Table 3 below.

[0148] [Tables3] Line EGF chemoattraction alone (% of control ± SEM) p-value EGF chemoattraction in combination (% of control + SEM) Peptide inhibitory effect (%) p-value Glioblastoma 8MG 154.91 + 8.38 0.0018 114.37 + 7.71 -40.55 0.0332 42MG 168.89 + 2.89 < 0.0001 119.41 + 8.81 -49.48 < 0.0001 U87 225.05 + 7.27 < 0.0001 121.87 + 8.37 -103.18 < 0.0001 GL15 166.54 + 6.58 0.0003 138.93 + 13.00 -27.61 0.0002 Pulmonary A549 241.74 + 4.07 < 0.0001 219.60 + 6.29 -22.14 < 0.0001 Breast MDA-MB-23 1 226.07 + 4.80 < 0.0001 169.53 + 7.90 -56.54 < 0.0001 Prostatic LnCAP 368.17 + 7.10 < 0.0001 111.63 + 8.42 -256.54 < 0.0001

[0149] The sequence construct SEQ ID NO: 35 strongly and significantly prevents directional migration evoked by 50 ng / ml EGF in the 8MG, 42MG and U87 GB and LnCAP prostate cancer lines that migrate in response to EGF in control condition when applied alone (-40.55%, p = 0.0332; -49.48%, p < 0.0001; -103.18%, p < 0.0001 and -256.54%, p < 0.0001 respectively). In the GB lines GL15, A549 lung cancer and MDA-MB-231 breast cancer, the construct with sequence SEQ ID NO: 35 partially prevents directional migration evoked by 50 ng / ml EGF (-27.61%, p = 0.0002; -22.14%, p < 0.0001 and -56.54%, p < 0.0001 respectively). The construct with sequence SEQ ID NO: 35 is indeed an effective compound that can inhibit directional migration of solid cancer lines responding to chemoattractant gradients of EGF.

[0150] Example 4: Effect of the construct of the invention mimicking a segment of FlnA involved in binding to UT (SEQ ID NO: 29) on cell migration of GB lines 8MG, 42MG, U87 and GL15, A549 lung cancer, MDA-MB-231 breast cancer and LnCAP prostate cancer in response to 109 M of UII peptide.

[0151] At T0, 30,000 GB 8MG, 42MG, U87 and GL15 cells and 75,000 A549 lung cancer cells, 100,000 MDA-MB-231 breast cancer cells and 75,000 LnCAP prostate cancer cells were seeded on the porous membrane (8 μm) of the upper Boyden chamber in the presence of 100 nM of the construct of sequence SEQ ID NO: 29. A homogeneous concentration of UII 109 M is placed in the lower chambers. After 24 h, the cells of the upper chamber are removed, and those of the lower chamber are fixed and the nuclei are labeled with DAPI (4',6-diamino-2-phenylindole) then the membranes are cut and mounted between slide and coverslip and eight microphotographs are taken per membrane. The number of cells / field was quantified semi-automatically using the Image! image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are summarized in Table 4 below.As for all other experiments, Statistical test: Two-way ANOVA; Sidak post-test, 2 membranes per condition and n=8 fields per membrane. Line UII chemoattraction alone (% of control ± SEM) p-value UII chemoattraction in combination (% of control ± SEM) Peptide inhibitory effect (%) p-value Glioblastoma 8MG 155.78 + 8.83 0.0036 87.37 + 13.65 -68.41 0.0007 42MG 160.81+4.69 < 0.0001 134.10 + 7.66 -26.72 0.0015 U87 154.11 + 4.53 < 0.0001 90.94 + 9.41 -63.17 0.0001 GL15 166.07 + 4.35 < 0.0001 74.27+ 11.98 -91.8 0.0001 Pulmonary A549 99.15 + 13.31 0.955 104.46 + 14.03 5.32 0.0231 Breast MDA-MB-23 1 70.13 + 10.15 0.0001 52.69 + 8.52 -17.44 0.0001 Prostatic LnCAP 240.02 + 10.47 0.000 1 101.87 + 6.94 -138.15 0.0022

[0153] The sequence construct SEQ ID NO: 29 completely and significantly prevents the directional migration evoked by 109 M of UII in the 8MG, U87 and GL15 lines of GB and LnCAP of prostate cancer which respond positively to UII in control condition when applied alone (-68.41%, p = 0.0007; -63.17%, p < 0 .0001; -91.80%, p < 0 .0001 and -138.15%, p = 0.0022 respectively). In addition, it partially prevents the migration evoked by 109 M of UII in the 42MG line of GB (-26.72%, p = 0.0015). The sequence construct SEQ ID NO: 29 is in fact an effective compound that can inhibit the directional migration of solid cancer lines responding to chemoattractant gradients of UII peptide.

[0154] Example 5: Effect of the construct of the invention mimicking a segment of FlnA involved in binding to UT (SEQ ID NO: 29) on cell migration of GB lines 8MG, 42MG, U87 and GL15, A549 lung cancer, MDA-MB-231 breast cancer and LnCAP prostate cancer in response to 50 ng / ml of EGF (Epidermal Growth Factor). At T0, 30,000 GB 8MG, 42MG, U87 and GL15 cells and 75,000 A549 lung cancer cells, 100,000 MDA-MB-231 breast cancer cells and 75,000 LnCAP prostate cancer cells were seeded onto the porous membrane (8 μm) of the upper Boyden chamber in the presence of 100 nM of the construct of sequence SEQ ID NO: 29. A homogeneous concentration of EGF 50 ng / ml is placed in the lower chambers.After 24 hours, the cells in the upper chamber were removed, and those in the lower chamber were fixed and the nuclei were labeled with DAPI (4',6-diamino-2-phenylindole), then the membranes were cut and mounted between slide and coverslip, and eight microphotographs were taken per membrane. The number of cells / field was quantified semi-automatically using the ImageJ image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are summarized in Table 5 below. Line EGF chemoattraction alone (% of control ± SEM) p-value EGF chemoattraction in combination (% of control + SEM) Peptide inhibitory effect (%) p-value Glioblastoma 8MG 154.91 + 8.38 0.0018 115.32 + 11.88 -39.59 0.0933 42MG 168.89 + 2.89 < 0.0001 170.02 + 5.33 -1.13 0.2295 U87 225.05 + 7.27 < 0.0001 161.46 + 7.49 -63.59 0.0022 GL15 166.54 + 6.58 0.0003 128.79+ 11.72 -37.75 < 0.0001 Pulmonary A549 241.74 + 4.07 < 0.0001 238.17 + 7.86 3.57 < 0.0001 Breast MDA-MB-23 1 226.07 + 4.80 < 0.0001 244.33 + 5.98 18.27 < 0.0001 Prostatic LnCAP 368.17 + 7.10 < 0.0001 194.45 + 5.86 -173.72 0.1626

[0156] The sequence construct SEQ ID NO: 29 partially prevents directional migration evoked by 50 ng / ml EGF in GB lines U87 and GL15 that respond positively to EGF in control conditions when applied alone (-63.59%, p = 0.0022 and -37.75%, p < 0.0001 respectively). The sequence construct SEQ ID NO: 29 is in fact a partially effective compound that can inhibit directional migration of solid cancer lines responding to chemoattractant gradients of EGF.

[0157] Example 6: Effect of the construct of the invention mimicking a segment of UT involved in binding to FlnA (SEQ ID NO: 37) on cell migration of GB lines 8MG, 42MG, U87 and U251 in response to 109 M of UII peptide. At T0, 30,000 GB cells 8MG, 42MG, U87 and U251 were seeded on the porous membrane (8 μm) of the upper Boyden chamber in the presence of 100 nM of the construct of sequence SEQ ID NO: 37. A homogeneous concentration of 109 M UII is placed in the lower chambers. After 24 hours, the cells of the upper chamber are eliminated, and those of the lower chamber are fixed and the nuclei labeled with DAPI (4',6-diamino-2-phenylindole) then the membranes are cut and mounted between slide and coverslip and eight microphotographs are taken per membrane. The number of cells / field is quantified semi-automatically using the ImageJ image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are grouped in the following Table 6.

[0158] [Tableauxô] Line UII chemoattraction alone (% of control ± SEM) p-value UII chemoattraction in combination (% of control ± SEM) Peptide inhibitory effect (%) p-value Glioblastoma 8MG 209.99 + 22.69 < 0.0001 86.01 + 14.28 -123.98 < 0.0001 42MG 204.87 + 9.22 < 0.0001 89.51 + 7.26 -115.36 < 0.0001 U87 199.76 + 5.48 < 0.0001 88.80 + 11.15 -110.96 < 0.0001 U251 154.48 + 7.14 0.003 93.98 + 10.97 -60.5 < 0.0001

[0159] The sequence construct SEQ ID NO: 37 completely and significantly prevents the directional migration evoked by 109 M of UII in the 8MG, 42MG, U87 and U251 GB lines that respond positively to UII in control condition when applied alone (-123.98%, p < 0.0001; -115.36%, p < 0.0001; -110.96%, p < 0.0001 and -60.50%, p < 0.0001 respectively). The sequence construct SEQ ID NO: 37 is indeed an effective compound that can inhibit the directional migration of GB lines responding to chemoattractant gradients of UII peptide.

[0160] Example 7: Effect of the construct of the invention mimicking a segment of UT involved in binding to FlnA (SEQ ID NO: 36) on cell migration of GB lines 8MG, 42MG, U87 and U251 in response to 109 M of UII peptide. At T0, 30,000 8MG, 42MG, U87 and U251 glioblastoma cells were seeded on the porous membrane (8 μm) of the upper Boyden chamber in the presence of 100 nM of the construct of sequence SEQ ID NO: 36. A homogeneous concentration of UII 10 9 M is placed in the lower chambers. After 24 hours, the cells in the upper chamber are removed, and those in the lower chamber are fixed and the nuclei labeled with DAPI (4',6-diamino-2-phenylindole) then the membranes are cut and mounted between slide and coverslip and eight microphotographs are taken per membrane.The number of cells / field was quantified semi-automatically using ImageJ image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are grouped in the following Table 7.

[0161] [Tables?] Line UII chemoattraction alone (% of control ± SEM) p-value UII chemoattraction in combination (% of control ± SEM) Peptide inhibitory effect (%) p-value Glioblastoma 8MG 209.99 + 22.69 < 0.0001 54.21 + 11.01 -155.78 < 0.0001 42MG 204.87 + 9.22 < 0.0001 104.02 + 5.10 -100.85 < 0.0001 U87 199.76 + 5.48 < 0.0001 133.31 + 5.49 -66.45 0.0211 U251 154.48 + 7.14 0.003 210.79 + 10.94 56.31 0.9025

[0162] The sequence construct SEQ ID NO: 36 completely and significantly prevents directional migration evoked by 109 M UII in the 8MG and 42MG lines that migrate in response to UII in control condition when applied alone (-155.78%, p < 0.0001 and -100.85%, p < 0.0001 respectively). In addition, the sequence construct SEQ ID NO: 36 partially prevents migration evoked by 109 M UII in the U87 line (-66.45%, p = 0.0211). The sequence construct SEQ ID NO: 36 is indeed a partially effective compound that can inhibit directional migration of GB lines responding to chemoattractant gradients of UII peptide.

[0163] Example 8: Effect of the construct of the invention mimicking a segment of FlnA involved in binding to UT (SEQ ID NO: 32) on cell migration of GB lines 8MG, 42MG, U87 and U251 in response to 109 M of UII peptide.

[0164] At T0, 30,000 GB 8MG, 42MG, U87 and U251 cells were seeded on the porous membrane (8 μm) of the upper Boyden chamber in the presence of 100 nM of the construct of sequence SEQ ID NO: 32. A homogeneous concentration of UII 109 M is placed in the lower chambers. After 24 h, the cells of the upper chamber are eliminated, and those of the lower chamber are fixed and the nuclei are labeled with DAPI (4',6-diamino-2-phenylindole) then the membranes are cut and mounted between slide and coverslip and eight microphotographs are taken per membrane. The number of cells / field is quantified semi-automatically using the Image! image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are grouped in the following Table 8. Line UII chemoattractio n alone (% of control ± SEM) p-value UII chemoattractio n in combination (% of control ± SEM) Peptide inhibitory effect (%) p-value Glioblastoma 8MG 209.99 + 22.69 0.0001 93.67 + 15.01 -116.32 < 0.0001 42MG 204.87 + 9.22 0.0001 107.47 + 7.71 -97.4 0.0009 U87 199.76 + 5.48 0.0001 80.06 + 5.06 -119.71 < 0.0001 U251 154.48 + 7.14 0.0003 108.36 + 7.58 -46.12 < 0.0001

[0166] The sequence construct SEQ ID NO: 32 completely and significantly prevents the directional migration evoked by 109 M of UII in the 8MG, 42MG, U87 and U251 GB lines that respond positively to UII in control condition when applied alone (-116.32%, p < 0.0001; -97.40%, p = 0.0009; -119.71%, p < 0.0001 and -46.12%, p < 0.0001 respectively). The sequence construct SEQ ID NO: 32 is indeed an effective compound that can inhibit the directional migration of GB lines responding to chemoattractant gradients of UII peptide.

[0167] Example 9: Effect of the construct of the invention mimicking a segment of FlnA involved in binding to UT (SEQ ID NO: 33) on cell migration of GB lines 8MG, 42MG, U87 and U251 in response to 109 M of UII peptide. At T0, 30,000 cells of 8MG, 42MG, U87 and U251 were seeded on the porous membrane (8 μm) of the upper Boyden chamber in the presence of 100 nM of the construct of sequence SEQ ID NO: 33. A homogeneous concentration of 109 M UII is placed in the lower chambers. After 24 hours, the cells in the upper chamber were removed, and those in the lower chamber were fixed and the nuclei were labeled with DAPI (4',6-diamino-2-phenylindole), then the membranes were cut and mounted between slide and coverslip and eight microphotographs were taken per membrane. The number of cells / field was quantified semi-automatically using the Image! image analysis software (8 fields analyzed per membrane, 2 membranes per condition).The results are grouped in the following table 9: . Line UII chemoattraction alone (% of control ± SEM) p-value UII chemoattraction in combination (% of control ± SEM) Peptide inhibitory effect (%) p-value Glioblastoma 8MG 209.99 ± 22.69 0.0001 104.50 + 10.56 -105.48 < 0.0001 42MG 204.87 ± 9.22 0.0001 100.58 + 8.75 -104.29 0.0037 U87 199.76 ± 5.48 0.0001 174.93 + 5.87 -24.83 0.0037 U251 154.48 + 7.14 0.0003 95.95 + 10.54 -58.53 < 0.0001

[0169] The sequence construct SEQ ID NO: 33 completely and significantly prevents the directional migration evoked by 109 M of UII in the 8MG, 42MG and U251 GB lines that respond positively to UII in control condition when applied alone (-105.48%, p < 0.0001; -104.29%, p = 0.0037 and -58.53%, p < 0.0001 respectively). In addition, the sequence construct SEQ ID NO: 33 partially prevents the migration evoked by 109 M UII in the U87 line (-24.83%, p = 0.0037). The sequence construct SEQ ID NO: 33 is indeed an effective compound that can inhibit the directional migration of GB lines responding to chemoattractant gradients of UII peptide.

[0170] Example 10: Effect of the construct of the invention mimicking a segment of FlnA involved in binding to UT (SEQ ID NO: 31) on cell migration of GB lines 8MG, 42MG, U87 and U251 in response to 109 M of UII peptide.

[0171] At T0, 30,000 GB 8MG, 42MG, U87 and U251 cells were seeded on the porous membrane (8 μm) of the upper Boyden chamber in the presence of 100 nM of the construct of sequence SEQ ID NO: 31. A homogeneous concentration of UII 109 M is placed in the lower chambers. After 24 hours, the cells of the upper chamber are eliminated, and those of the lower chamber are fixed with DAPI (4',6-diamino-2-phenylindole) then the membranes are cut and mounted between slide and coverslip and 8 microphotographs are taken per membrane. The number of cells / field is quantified semi-automatically using the Image! image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are grouped in the following Table 10. Line UII chemoattraction alone (% of control ± SEM) p-value UII chemoattraction in combination (% of control ± SEM) Peptide inhibitory effect (%) p-value Glioblastoma 8MG 209.99 ± 22.69 < 0.0001 201.11 + 11.50 -8.88 0.0001 42MG 204.87 ± 9.22 < 0.0001 200.29 + 5.21 -4.57 0.0609 U87 199.76 ± 5.48 < 0.0001 162.60 + 3.26 -37.17 0.0164 U251 154.48 + 7.14 0.0003 60.88 + 11.81 -93.6 < 0.0001

[0173] The construct of sequence SEQ ID NO: 31 completely and significantly prevents the directional migration evoked by UII 109 M in the U251 GB line which responds positively to UII in control condition when applied alone (-93.60%, p < 0.0001). In addition, the construct of sequence SEQ ID NO: 31 partially prevents the migration evoked by UII 109 M in the U87 line (-37.17%, p = 0.0164). The construct SEQ ID NO: 31 is in fact a partially effective compound which can inhibit the directional migration of GB lines responding to chemoattractant gradients of UII peptide.

[0174] Example 11: Effect of the construct of the invention mimicking a segment of FlnA involved in binding to UT (SEQ ID NO: 53) on cell migration of GB lines 8MG and U87 in response to UII 109 M.

[0175] At T0, 30,000 GB 8MG and U87 cells were seeded onto the porous membrane (8 μm) of the upper Boyden chamber in the presence of 10 μM of the construct with sequence SEQ ID NO: 53. A homogeneous concentration of UII 109 M is placed in the lower chambers. After 24 hours, the cells in the upper chamber are removed, and those in the lower chamber are fixed with DAPI (4',6-diamino-2-phenylindole), then the membranes are cut and mounted between slide and coverslip and 8 microphotographs are taken per membrane. The number of cells / field is quantified semi-automatically using the Image! image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are grouped in the following Table 11: Line UII chemoattraction alone (% of control ± SEM) p-value UII chemoattraction in combination (% of control ± SEM) Peptide inhibitory effect (%) p-value Glioblastoma 8MG 245.05 ± 18.21 0.0001 118 ± 11.21 -127.06 0.0001 U87 245.24 ± 8.24 0.0001 151.59 + 9.29 -93.65 0.0001

[0177] The sequence construct SEQ ID NO: 53 significantly prevents directional migration evoked by UII 109 M in 8MG and U87 GB lines that respond positively to UII in control condition when applied alone (-127.06%, p < 0.0001 and -93.65%, p < 0.0001 respectively). The construct SEQ ID NO: 53 is indeed an effective compound that can inhibit directional migration of GB lines responding to chemoattractant gradients of UII peptide independently of binding to the UT receptor.

[0178] Example 12: Effect of the construct of the invention mimicking a segment of FlnA involved in binding to UT (SEQ ID NO: 54) on cell migration of GB lines 8MG and U87 in response to UII 109 M. At T0, 30,000 GB 8MG and U87 cells were seeded on the porous membrane (8 μm) of the upper Boyden chamber in the presence of 10 μM of the construct of sequence SEQ ID NO: 54. A homogeneous concentration of UII 109 M is placed in the lower chambers. After 24 hours, the cells of the upper chamber are removed, and those of the lower chamber are fixed with DAPI (4',6-diamino-2-phenylindole) then the membranes are cut and mounted between slide and coverslip and 8 microphotographs are taken per membrane. The number of cells / field was quantified semi-automatically using the Image! image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are summarized in Table 12 below. Line UII chemoattraction alone (% of control ± SEM) p-value UII chemoattraction in combination (% of control ± SEM) Peptide inhibitory effect (%) p-value Glioblastoma 8MG 245.05 ± 18.21 < 0.0001 52.15 + 5.04 -192.9 0.0001 U87 245.24 ± 8.24 < 0.0001 139.12 + 9.21 -106.12 0.0002

[0180] The sequence construct SEQ ID NO: 54 significantly prevents directional migration evoked by UII 109 M in 8MG and U87 GB lines that respond positively to UII in control condition when applied alone (-192.90%, p < 0.0001 and -106.12%, p = 0.0002 respectively). The construct SEQ ID NO: 54 is indeed an effective compound that can inhibit directional migration of GB lines responding to chemoattractant gradients of UII peptide independently of binding to the UT receptor.

[0181] Example 13: Effect of the construct of the invention mimicking a segment of FlnA involved in binding to UT (SEQ ID NO: 55) on cell migration of GB lines 8MG and U87 in response to 109 M of UII peptide.

[0182] At T0, 30,000 GB 8MG and U87 cells were seeded onto the porous membrane (8 μm) of the upper Boyden chamber in the presence of 10 μM of the construct with sequence SEQ ID NO: 55. A homogeneous concentration of UII 109 M is placed in the lower chambers. After 24 hours, the cells in the upper chamber are removed, and those in the lower chamber are fixed with DAPI (4',6-diamino-2-phenylindole), then the membranes are cut and mounted between slide and coverslip and 8 microphotographs are taken per membrane. The number of cells / field is quantified semi-automatically using the Image! image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are grouped in the following Table 13. Line UII chemoattraction alone (% of control ± SEM) p-value UII chemoattraction in combination (% of control ± SEM) Peptide inhibitory effect (%) p-value Glioblastoma 8MG 245.05 + 18.21 0.0001 71.29 + 14.40 -173.77 0.0001 U87 245.24 + 8.24 0.0001 148.83 + 9.75 -96.41 0.0001

[0184] The sequence construct SEQ ID NO: 55 significantly prevents directional migration evoked by UII 109 M in 8MG and U87 GB lines that respond positively to UII in control condition when applied alone (-173.77%, p < 0.0001 and -96.41%, p < 0.0001 respectively). The construct SEQ ID NO: 55 is indeed an effective compound that can inhibit directional migration of GB lines responding to chemoattractant gradients of UII peptide independently of binding to the UT receptor.

[0185] Example 14: Effect of the construct of the invention mimicking a segment of FlnA involved in binding to T UT (SEQ ID NO: 48) on cell migration of the GB U87 line in response to UII 109 M. At T0, 30,000 GB U87 cells were seeded on the porous membrane (8 μm) of the upper Boyden chamber in the presence of 10 μM of the construct of sequence SEQ ID NO: 48. A homogeneous concentration of UII 109 M is placed in the lower chambers. After 24 hours, the cells of the upper chamber are removed, and those of the lower chamber are fixed with DAPI (4',6-diamino-2-phenylindole) then the membranes are cut and mounted between slide and coverslip and 8 microphotographs are taken per membrane. The number of cells / field was quantified semi-automatically using the Image! image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are summarized in Table 14 below. Line UII chemoattraction alone (% of control ± SEM) p-value UII chemoattraction in combination (% of control ± SEM) Peptide inhibitory effect (%) p-value Glioblastoma U87 166.94 + 9.63 < 0.0001 147.86 + 11.00 -19.08 0.3674

[0187] The construct of sequence SEQ ID NO: 48 partially prevents the directional migration evoked by UII 109 M in the U87 GB line which responds positively to UII in control condition when applied alone (-19.08%, p = 0.3674). The construct SEQ ID NO: 48 is in fact a non-effective compound for the inhibition of the directional migration of GB lines responding to chemoattractant gradients of UII peptide independently of binding to the UT receptor.

[0188] Example 15: Effect of the construct of the invention mimicking a segment of FlnA involved in binding to UT (SEQ ID NO: 51) on cell migration of the GB U87 line in response to UII 109 M. At T0, 30,000 GB U87 cells were seeded on the porous membrane (8 μm) of the upper Boyden chamber in the presence of 10 μM of the construct of sequence SEQ ID NO: 51. A homogeneous concentration of UII 109 M is placed in the lower chambers. After 24 hours, the cells of the upper chamber are removed, and those of the lower chamber are fixed with DAPI (4',6-diamino-2-phenylindole) then the membranes are cut and mounted between slide and coverslip and 8 microphotographs are taken per membrane. The number of cells / field was quantified semi-automatically using the Image! image analysis software (8 fields analyzed per membrane, 2 membranes per condition). The results are summarized in Table 15 below.

[0189] [Tables 15] Line UII chemoattraction alone (% of control ± SEM) p-value UII chemoattraction in combination (% of control ± SEM) Peptide inhibitory effect (%) p-value Glioblastoma U87 166.94 + 9.63 0.0001 126.79 + 9.31 -40.16 0.3674

[0190] The sequence construct SEQ ID NO: 51 partially prevents UII 109 M-evoked directional migration in the GB U87 line that responds positively tively to UII in control condition when applied alone (-40.16%, p = 0.3674). The construct SEQ ID NO: 51 is in fact a non-effective compound for the inhibition of directional migration of GB lines responding to chemo-attractant gradients of UII peptide independently of binding to the UT receptor.

[0191] Example 16: Influence of the construct SEQ ID NO: 35 mimicking a sequence of the UT binding FlnA on the viability of U251, 8MG, 42MG, U87 and GL15 cells of GB, A549, HCC827 and PC9 of lung cancer, MDA-MB-231 of breast cancer and LnCAP of prostate cancer.

[0192] At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of sequence construct SEQ ID NO: 35 tested from 105 M to 10 12 M. The cell density is evaluated at 24h, 48h and 72h using the CellTiter-Glo 3D kit (Promega). The results are grouped in Table 16. Lignée IC50 Inhib.Max (%) C-Max (|iM) p-value Inhib.Min (%) C-Min (|iM) p-value (pM) Glioblastome U251 24h >100 39,62 10 <0,0001 18,33 1 0,039 48h >100 52,02 10 <0,0001 25,81 1 0,0034 72h 6,23 + 4,23 61,14 10 <0,0001 33,18 1 0,0073 8MG 24h 28,69 + 20,01 27,32 10 0,3608 27,32 10 0,3608 48h 13,47 ±6,63 50,22 10 <0,0001 22,74 1 0,0057 72h 1,06 + 0,69 74,99 10 <0,0001 48,87 1 0,0001 42MG 24h 20 + 10,07 34,93 10 0,9859 34,93 10 0,9859 48h 7,81 + 2,08 52,06 10 0,0032 28,53 1 0,0164 72h 4,77 + 1,31 58,07 10 0,0021 35,04 1 0,0128 U87 24h 22,44 + 6,05 37,98 10 0,0002 37,98 10 0,0002 48h 5,95 + 1,57 55,75 10 <0,0001 21,17 1 0,0324 72h 1,81 + 0,45 72,57 10 <0,0001 41,36 1 0,0011 GL15 24h 53,5 + 51,91 49,98 10 <0,0001 27,22 0,01 0,0222 48h 3,78 + 1,02 63,56 10 0,0007 38,99 1 0,0093 72h 1,93 + 0,84 79,6 10 0,0006 56,63 1 0,0059 Pulmonary A549 24h 14.79 ±5.7 42.08 10 0.1662 42.08 10 0.1662 48h 11.26 ±4.3 50.05 10 0.0007 23.76 1 0.0186 72h 3.83 ± 1.46 58.16 10 0.0008 39.22 1 0.0034 HCC827 24h 6.55 ± 1.73 54.88 10 <0.0001 29.08 1 0.0039 48h 4.18 ± 0.42 67.83 10 0.0004 22.26 1 0.0234 72h 3.17 ± 0.24 77.72 10 <0.0001 21.48 1 0.0006 PC9 24h 7.35 ± 1.24 55.06 10 0.0057 55.06 10 0.0057 48h 4.05 ± 5.82 63.15 10 0.0059 63.15 10 0.0059 72h 3.04 ± 0.27 66.92 10 <0.0001 34.46 0.01 0.0104 Breast MDA-MB-231 24h 13.68 ±3.67 45.86 10 0.0004 14.91 1 0.0484 48h 10.57 ±2.68 49.1 10 0.0005 23.24 1 0.0174 72h 3.93 ± 1.03 60.26 10 <0.0001 35.92 1 0.0004 Prostatic LnCAP 24h 4.94 ± 0.51 63.26 10 0.0016 23.01 1 0.0175 48h 4.11 ± 0.34 70.12 10 0.2214 70.12 10 0.2214 72h 2.99 ± 0.30 74.63 10 0.0093 74.63 10 0.0093

[0194] The sequence construct SEQ ID NO: 35 exhibits inhibitory effects which increase over time on all of the solid cancer lines cited above, with particularly significant inhibitory effects at 72 hours. These inhibitory effects are maximal at the concentration of 10 pM with viability inhibition percentages of 61.14% (p < 0.0001), 74.99% (p < 0.0001), 58.07% (p = 0.0021), 72.57% (p < 0.0001), 79.60% (p = 0.0006), 58.16% (p = 0.0008), 77.72% (p < 0.0001), 66.92% (p < 0.0001), 60.26% (p < 0.0001), 74.63% (0.0093) for the lines U251, 8MG, 42MG, U87, GL15, A549, HCC827, PC9, MDA-MB-231 and LnCAP respectively.The minimal inhibition effects are observed at 1 pM in U251, 8MG, 42MG, U87, GL15, A549, HCC827 and MDA-MB-231 lines, they are more specifically 33.18% (p = 0.0073), 48.87% (p < 0.0001), 35.04% (p = 0.0128), 41.36% (p = 0.0011), 56.63% (p = 0.0059), 39.22% (p = 0.0034), 21.48 (p = 0.0006), 35.92% (p = 0.0004) respectively. The inhibition is 34.46% (p = 0.0104) at 0.01 pM in the PC9 line. At 72h, the construct of sequence SEQ ID NO: 35 presents IC50s in the order of pM between 1.06 and 6.23 pM. The construct of sequence SEQ ID NO: 35 shows inhibitory effects on the viability of GB, lung and breast cancer lines.

[0195] Example 17: Influence of the construction of sequence SEQ ID NO: 29 mimicking a sequence of FlnA binding FUT on the viability of U251, 8MG, 42MG, U87 and GL15 cells of GB, A549, HCC827 and PC9 of lung cancer, MDA-MB-231 of breast cancer and LnCAP of prostate cancer.

[0196] At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of construct SEQ ID NO: 29 tested from 105 M to 10 12 M. The cell density is evaluated at 24h, 48h and 72h using the CellTiter-Glo 3D kit (Promega). The results are grouped in Table 17. The construct of sequence SEQ ID NO: 29 exhibits inhibitory effects which become more pronounced over time on all the solid cancer lines cited above, with particularly significant inhibitory effects at 72h. These inhibitory effects are maximal at the concentration of 10 pM with inhibition percentages of 49.48% (p = 0.0036), 46.28% (p < 0.0001), 44.39% (p = 0.0035), 46.41% (p = 0.0209), 43.73% (p = 0.0014), 53.19% (p < 0.0001), 49.25% (p = 0.002), 61.68% (p = 0.0024) for the lines U251, 8MG, U87, A549, HCC827, PC9, MDA-MB-231 and LnCAP respectively.The construct, however, shows no effect at 72 hours in the 42MG and GL15 lines. Significant inhibition of 21.94% (p = 0.0084), 18.76% (p = 0.0007) and 19.77% (p = 0.0251) is observed in the 8MG, PC9 and LnCAP lines, respectively, from a concentration of 1 pM. At 72 hours, the construct with sequence SEQ ID NO: 29 shows IC50s of the order of ten pM, between 5.17 and 25.18 pM for the responding lines. Table 17 lists the experimental results. experimental data on the effects of construct SEQ ID NO 29 on the viability of different lines of glioblastoma (U251, 8MG, 42MG, U87, GL15), lung (A549, HCC827 PC9), breast (MDA-MB-231) and prostate (LnCAP) cancers. Statistical test: Kruskal-Wallis; Dunn's post-test, n = 2 or 3 independent experiments per line in triplicate. Lignée IC50 (pM) Inhib.Max (%) C-Max (|iM) p-value Inhib.Min (%) C-Min (|iM) p-value Glioblastome U251 24h >100 32,05 10 0,007 20,22 1 0,007 48h 68,36 + 61,01 37,44 10 <0,0001 26,46 1 0,0045 72h 10,34 + 5,07 49,48 10 0,0036 49,48 10 0,0036 8MG 24h 84,55 + 69,61 23,83 10 0,0125 23,83 10 0,0125 48h 78,26 + 177 16,91 10 0,3874 16,91 10 0,3874 72h 25,18 + 18,90 46,28 10 <0,0001 21,94 1 0,0084 42MG 24h 55,11 + 40,07 29,54 10 0,0734 29,54 10 0,0734 48h 40,5 + 27,53 42,65 10 <0,0001 21,5 1 0,0021 72h 18,94 + 8,03 37,14 10 0,1831 37,14 10 0,1831 U87 24h 81.67 + 59.90 27.31 10 0.0005 13.11 1 0.0115 48h >100 23.32 10 >0.9999 23.32 10 >0.9999 72h 17.14 + 9.35 44.39 10 0.0035 44.39 10 0.0035 GL15 24h >100 24.65 10 0.0157 14.56 10-8 M 0.0142 48h >100 29.96 10 0.0008 29.96 10 0.0008 72h >100 26.48 10 0.6504 26.48 10 0.6504 Pulmonary A549 24h >100 29.18 10 0.4901 29.18 10 0.4901 48h 14.95 + 3.99 42.44 10 0.0164 42.44 10 0.0164 72h 11.12 + 3.18 46.41 10 0.0209 46.41 10 0.0209 HCC827 24h 11.62 + 2.68 47.43 10 0.0003 47.43 10 0.0003 48h 12.86 + 2.10 44.63 10 0.0078 44.63 10 0.0078 72h 13.99 + 2.57 43.73 10 0.0014 43.73 10 0.0014 PC9 24h 10.62 + 1.92 48.39 10 0.0023 48.39 10 0.0023 48h 9.41 + 1.32 50.42 10 0.0199 50.42 10 0.0199 72h 8.31 + 0.78 53.19 10 <0.0001 18.76 1 0.0007 Mammary MDA-MB-231 24h 15.44 + 4.76 43.28 10 0.0012 43.28 10 0.0012 48h 12.27 + 2.28 45.9 10 0.0031 45.9 10 0.0031 72h 10.41 + 2.14 49.25 10 0.002 49.25 10 0.002 Prostatic LnCAP 24h 7.51 + 1.43 54.62 10 0.0039 20.04 1 0.0423 48h 5.38 + 1.29 59.52 10 0.0816 59.52 10 0.0816 72h 5.60 + 0.40 61.68 10 0.0024 19.77 1 0.0251

[0198] Example 18: Influence of the construction of sequence SEQ ID NO: 37 mimicking a FUT sequence binding FlnA on the viability of U251, 8MG, 42MG, U87 and GL15 GB and A549 lung cancer cells.

[0199] At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of construct of sequence SEQ ID NO: 37 tested from 105 M to 10 12 M. The cell density is evaluated at 24h, 48h and 72h using the kit CellTiter-Glo 3D (Promega). The results are grouped in Table 18. The construct with sequence SEQ ID NO: 37 shows inhibitory effects increasing over time only in the GB U251 line with a maximum effect 72h, 10 pM of 89.40% (p = 0.0017) of inhibition of viability. The inhibitory properties of the construct with sequence SEQ ID NO: 37 are not very specific and suggest that the fusion of the constructs with sequences SEQ ID NO: 4 and SEQ ID NO: 8 is less effective than for its counterpart with sequence SEQ ID NO: 35 resulting from the fusion of constructs SEQ ID NO: 4 and SEQ ID NO: 9. The permeant sequence SEQ ID NO: 9 seems, in fact, decisive in relaying the inhibitory effects on cell viability of this construct.

[0200] Table 18 groups the experimental results of the effects of the construct SEQ ID NO 37 on the viability of different glioblastoma lines (U251, 8MG, 42MG, U87, GL15) and lung cancer (A549). Statistical test: Kruskal-Wallis; Dunn posttest, n = 2 or 3 independent experiments per line in triplicate. Glioblastoma lineage IC50 (pM) Inhib.Max (%) Gmux (pM ) p-value Inhib.Min (%) GmIh (pM ) p-value U251 24h >100 <5 10 >0.9999 <5 10 >0.9999 48h 23.6 + 21.78 58.41 10 0.0021 58.41 10 0.0021 72h 0.008 + 0.008 89.4 10 0.0017 89.4 10 0.0017 8MG 24h >100 13.59 10 >0.9999 13.59 10 >0.9999 48h >100 36.63 10 0.0114 36.63 10 0.0114 72h >100 33.08 10 >0.9999 33.08 10 >0.9999 42MG 24h >100 16.3 10 0.0318 16.3 10 0.0318 48h >100 19.46 10 0.1084 19.46 10 0.1084 72h >100 19.11 10 3589 19.11 10 3589 U87 24h >100 <5 10 >0.9999 <5 10 >0.9999 48h 30.38 + 31.05 29.2 10 0.4051 29.2 10 0.4051 72h 4.15 + 4.11 63.56 10 0.0697 63.56 10 0.0697 GL15 24h >100 <5 10 >0.9999 <5 10 >0.9999 48h >100 35.71 10 >0.9999 35.71 10 >0.9999 72h 4.66 + 8.71 63.68 10 0.1439 63.68 10 0.1439 Pulmonary A549 24h >100 <5 10 >0.9999 <5 10 >0.9999 48h >100 15.21 10 0.0193 15.21 10 0.0193 72h >100 16.65 10 0.0599 16.65 10 0.0599

[0202] Example 19: Influence of the construct SEQ ID NO: 32 mimicking a sequence of FlnA binding UT on the viability of U251, 8MG, 42MG, U87 and GL15 cells of GB and A549 of lung cancer.

[0203] At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of construct SEQ ID NO: 32 tested from 105 M to 10 12 M. The cell density is evaluated at 24h, 48h and 72h using the CellTiter-Glo 3D kit (Promega). The results are grouped in Table 19. Construct SEQ ID NO: 32 does not show any significant inhibitory effect on the lines tested. The absence of inhibitory properties of construct SEQ ID NO: 32 suggests that the association of constructs SEQ ID NO: 5 and SEQ ID NO: 8 of which it is the fusion is less effective than its counterpart SEQ ID NO: 29 resulting from the fusion of constructs SEQ ID NO: 5 and SEQ ID NO: 9. The permeant sequence SEQ ID NO: 9 seems to also decisive fact to relay the inhibitory effects on the cell viability of this construct. Statistical test: Kruskal-Wallis; Dunn post-test, n = 2 or 3 independent experiments per line in triplicate. Lignée Glioblastoma IC50 (pM) Inhib.Max (%) G Max (pM ) p-value Inhib.nMin (%) Gm1h (pM ) p-value U251 24h >100 <5 10 0,7171 <5 10 0,7171 48h >100 <5 10 0,4051 72h >100 <5 10 0,4051 <5 10 0,4051 8MG 24h >100 <5 10 >0,9999 <5 10 >0,9999 48h >100 <5 10 >0,9999 <5 10 >0,9999 72h >100 <5 10 >0,9999 <5 10 >0.9999 42MG 24h >100 <5 10 >0,9999 <5 10 >0,9999 48h >100 <5 10 >0,9999 <5 10 >0,9999 72h >100 <5 10 >0,9999 <5 10 >0,9999 U87 24h >100 <5 10 >0,9999 <5 10 >0,9999 48h >100 <5 10 0,6426 <5 10 0,6426 72h >100 <5 10 >0,9999 <5 10 >0,9999 GL15 24h >100 <5 10 >0,9999 <5 10 >0,9999 48h >100 <5 10 0,3172 <5 10 0,3172 72h >100 <5 10 >0,9999 <5 10 >0,9999 Pulmonaire A549 24h >100 <5 10 0,7171 <5 10 0,7171 48h >100 <5 10 >0,9999 <5 10 >0,9999 72h >100 <5 10 0,4051 <5 10 0,4051

[0205] Example 20: Influence of the construct of sequence SEQ ID NO: 30 mimicking a sequence of FlnA binding UT on the viability of U251, 8MG and 42MG GB cells. At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of construct SEQ ID NO: 30 tested from 105 M to 10 12 M. The cell density is evaluated at 24h, 48h and 72h using the CellTiter-Glo 3D kit (Promega). The results are grouped in Table 20. The construct of sequence SEQ ID NO: 30 exhibits inhibitory effects that increase over time only in the GB U251 line with a maximum effect at 72h, 10 pM of 73.67% (p = 0.0017) inhibition of viability. The lack of efficacy of the construct SEQ ID NO: 30 suggests that the interfering sequence of sequence SEQ ID NO: 5 forming part of its structure is not sufficient to relay inhibitory effects on the viability of glioblastoma lines.

[0206] Table 20 groups the effects of the construct SEQ ID NO 30 on the viability of different glioblastoma lines (U251, 8MG, 42MG). Statistical test: Kruskal-Wallis; Dunn post-test, n = 2 or 3 independent experiments per line in triplicate. Glioblastoma line IC50 (pM) Inhib.Max (%) C-Max (|iM) p-value Inhib.Min (%) GmIh (pM ) p-value U251 24h > 100 10.89 10 0.4562 10.89 10 0.4562 48h 65.07 + 55.97 36.47 10 0.0162 36.47 10 0.0162 72h 1.67 + 0.88 73.67 10 0.0017 38.76 1 0.0095 8MG 24h > 100 6.94 10 > 0.9999 6.94 10 > 0.9999 48h > 100 <5 10 > 0.9999 <5 10 > 0.9999 72h > 100 25.94 10 0.3589 25.94 10 0.3589 42MG 24h > 100 <5 10 > 0.9999 <5 10 > 0.9999 48h > 100 19.76 10 0.0697 19.76 10 0.0697 72h > 100 <5 10 > 0.9999 <5 10 > 0.9999

[0208] Example 21: Influence of the sequence construction SEQ ID NO: 34 mimicking a FUT sequence binding FlnA on the viability of GB U251 cells.

[0209] At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of construct SEQ ID NO: 34 tested from 105 M to 10 12 M. The cell density is evaluated at 24h, 48h and 72h using the CellTiter-Glo 3D kit (Promega). The results are grouped in Table 21. The construct of sequence SEQ ID NO: 34 exhibits inhibitory effects on early viability on the U251 line from 24h at 10 pM (50.15%, p = 0.0095) however unlike the other effective compounds of the invention its effects decrease at 72h to no longer be significant (p = 0.0513). Table 21 summarizes the effect of construct SEQ ID NO 34 on the viability of the U251 glioblastoma cell line. Statistical test: Kruskal-Wallis; Dunn's post-test, n = 3 independent experiments in triplicate. Lineage IC50 (pM) Inhib.Max (%) O Max (pM ) p-value Inhib.Min (%) G Min (pM ​​) p-value Glioblastoma U251 24h 3.79 + 5.97 50.15 10 0.0095 50.15 10 0.0095 48h 100 67.1 10 0.0438 67.1 10 0.0438 72h 4.11 + 6.74 43.02 10 0.0513 43.02 10 0.0513

[0211] Example 22: Influence the construction of sequence SEQ ID NO: 36 mimicking a FUT sequence binding FlnA on the viability of U251 glioblastoma cells.

[0212] At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of the construct of sequence SEQ ID NO: 36 tested from 105 M to 10 12 M. The cell density is evaluated at 24h, 48h and 72h using the CellTiter-Glo 3D kit (Promega). The results are grouped in Table 22. The construct of sequence SEQ ID NO: 36 exhibits inhibitory effects which increase over time on the viability of the GB U251 line with a maximum effect at 72h, 10 pM of 82.41% (p = 0.0025) inhibition of viability.

[0213] Table 22 groups the experimental results relating to the effect of the construct SEQ ID NO 36 on the viability of the U251 glioblastoma line. Statistical test: Kruskal-Wallis; Dunn's post-test, n = 3 independent experiments in triplicate. Lineage IC50 (pM) Inhib.Max (%) C-Max (|iM) p-value Inhib.Min (%) CMin (pM ​​) p-value Glioblastoma U251 24h >100 20.65 10 0.027 19.69 1 0.0095 48h 9.53 + 3.48 52.33 10 0.0017 20.13 1 0.0095 72h 0.0036 + 0.0026 82.41 10 0.0025 71.6 1 0.0066

[0215] Example 23: Influence of the sequence construction SEQ ID NO: 35 mimicking a FUT sequence binding FlnA on the viability of U251, 8MG, 42MG, U87 and GL15 cells of GB, A549, HCC827 and PC9 of lung cancer, MDA-MB-231 of breast cancer and LnCAP of prostate cancer in combination with standard therapies used in the clinic.

[0216] At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of the construct of sequence SEQ ID NO: 35 tested from 105 M to 10 12 M. In addition, the GB lines U251, 8MG, 42MG, U87 and GL15 receive a treatment of 950 pM of temozolomide (TMZ) and the lung cancer lines A549, HCC827, PC9 and breast cancer lines MDA-MB-231 are treated respectively with 20 pM, 0.008 pM, 0.020 pM and 20 pM of gefitinib. Finally, the prostate cancer line LnCAP receives a treatment of 1 nM of docetaxel. Cell density was assessed at 24, 48, and 72 hours using the CellTiter-Glo 3D kit (Promega). The results are summarized in Table 23.The construct of sequence SEQ ID NO: 35 administered at 10 pM exhibits significant additive inhibitory effects compared to the effects of TMZ in the GB lines U251, 8MG and U87, particularly significant at 72h, bringing the effect of TMZ alone from 38.3% to 86.51% (p < 0.0001); 80.11% to 92.80% (p = 0.0199) and 79.95% to 91.86% (p = 0.0398).

[0217] Table 23 groups the experimental results relating to the effect of the construct SEQ ID NO 35 on the viability of different lines of glioblastoma (U251, 8MG, 42MG, U87, GL15), lung cancer (A549, HCC827 PC9), breast cancer (MDA-MB-231) and prostate cancer (LnCAP) in combination with the corresponding conventional therapies. The lines U251, 8MG, 42MG, U87, GL15 of glio Blastoma cells were treated with 950 μM Temozolomide; lung cancer lines A549, HCC827, PC9 and breast cancer lines MDA-MB-231 were treated with 20 μM, 0.008 μM, 0.020 μM and 20 μM Gefitinib respectively; finally, prostate cancer line LnCAP was treated with 1 nM Docetaxel. Statistical test: Kruskal-Wallis; Dunn's post-test, n = 2 or 3 independent experiments per line in triplicate. Lignée Glioblastome Inhb. Chimi o(%) IC50 (pM) Inhib.Ma (%) C-Max (|iM) p-value Inhib.Min (%) C-Min (|iM) p-value U251 24h 1,34 27,2 + 37,14 51,73 10 0,0049 51,73 10 0,0049 48h 25,3 2,25 + 4,80 68,34 10 0,0002 68,34 10 0,0002 72h 38,3 0,0000 7 + 0,0000 7 86,51 10 <0,0001 68,09 1 0,0258 8MG 24h 14,2 >100 35,68 10 0,3966 35,68 10 0,3966 48h 59,1 >100 74,4 10 0,7704 74,4 10 0,7704 72h 80,1 >100 92,8 10 0,0199 92,8 10 0,0199 42MG 24h 5,79 16,01 ±5,7 45,2 10 0,0251 45,2 10 0,0251 48h 56 >100 79,89 10 0,243 79,89 10 0,243 72h 77,9 >100 91,84 10 0,291 91,84 10 0,291 U87 24h 1,97 21,95 + 10,00 30,66 10 0,015 30,66 10 0,015 48h 28,9 >100 62,68 10 0,011 62,68 10 0,011 72h 80 >100 91,86 10 0,0398 91,86 10 0,0398 GL15 24h 5,36 11,32 + 6,4 45,95 10 0,0955 45,95 10 0,0955 48h 57 >100 79,35 10 0,38 79,35 10 0,38 72h 81,7 >100 94,88 10 0,2506 94,88 10 0,2506 Pulmonary A549 24h 21.8 >100 51.77 10 0.2787 51.77 10 0.2787 48h 34.9 2.9 + 9.6 64.66 10 >0.9999 64.66 10 >0.9999 72h 49.2 0.007+ 0.025 71.14 10 >0.9999 71.14 10 >0.9999 HCC827 24h 7.91 8.67 + 1.8 52.25 10 0.1885 52.25 10 0.1885 48h 1.82 5.93 + 0.78 61.03 10 0.0055 61.03 10 0.0055 72h 5.58 3.15 + 0.29 76.47 10 0.0028 76.47 10 0.0028 PC9 24h 14.8 6.16 + 1.88 57.63 10 0.0132 57.63 10 0.0132 48h 48.6 >100 77.06 10 0.0039 77.06 10 0.0039 72h 76 >100 91.44 10 0.0009 91.44 10 0.0009 Mammary MDA-MB-2 31 24h 32.3 >100 56.52 10 0.546 56.52 10 0.546 48h 54.7 >100 71.94 10 0.1742 71.94 10 0.1742 72h 68.9 >100 81.91 10 >0.9999 81.91 10 >0.9999 Prostatic LnCAP 24h 2.02 7.13 + 1.2 59.18 10 0.6007 59.18 10 0.6007 48h 8.64 3.40 + 0.54 72.13 10 0.5771 72.13 10 0.5771 72h 23.3 1.56 + 1.01 79.67 10 0.0955 79.67 10 0.0955

[0219] In the lung cancer lines HCC827 and PC9, the construct also exhibits an additive effect to the effect of gefitinib at 72h, bringing the inhibition of viability induced by gefitinib from 5.58% to 76.47% (p = 0.0028) and from 76.00% to 91.44% (p = 0.0009), respectively. The additive effect of the compound of sequence SEQ ID NO: 35 to TMZ and gefitinib is particularly interesting for a combined application with chemotherapy or with targeted therapy in the clinic in a patient.

[0220] Example 24: Influence of the sequence construction SEQ ID NO: 29 mimicking a UT-binding FlnA sequence on the viability of U251, 8MG, 42MG, U87 and GL15 cells of GB, A549, HCC827 and PC9 of lung cancer, MDA-MB-231 of breast cancer and LnCAP of prostate cancer in combination with standard therapies used in the clinic.

[0221] At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of the construct of sequence SEQ ID NO: 29 tested from 105 M to 10 12 M. In addition, the GB lines U251, 8MG, 42MG, U87 and GL15 receive a treatment of 950 pM of temozolomide (TMZ) and the lung cancer lines A549, HCC827, PC9 and breast cancer lines MDA-MB-231 are treated respectively with 20 pM, 0.008 pM, 0.020 pM and 20 pM of gefitinib. Finally, the prostate cancer line LnCAP receives a treatment of 1 nM of docetaxel. Cell density was assessed at 24, 48, and 72 hours using the CellTiter-Glo 3D kit (Promega). The results are summarized in Table 24.The construct of sequence SEQ ID NO: 29 administered at 10 pM presents on the GB lines U251 and 8MG significant additive inhibitory effects to the effect of TMZ particularly important at 72h bringing the effect of TMZ alone from 41.68% to 80.07% (p = 0.0137) and 78.26% to 88.86% (p = 0.0108) in the lines U251 and 8MG respectively. In the lung cancer line PC9, the construct also presents an additive effect to gefitinib at 72h bringing the inhibition of viability induced by gefitinib from 76.00% to 89.80% (p = 0.0168). The additive effect of the compound SEQ ID NO: 29 to TMZ and to . Gefitinib is not systematic in all GB and lung cancer lines.

[0222] Table 24 groups the experimental results relating to the effect of the construct SEQ ID NO 29 on the viability of different glioblastoma (U251, 8MG, 42MG, U87, GL15), lung (A549, HCC827 PC9), breast (MDA-MB-231) and prostate (LnCAP) cancer lines in combination with the corresponding conventional therapies. The glioblastoma lines U251, 8MG, 42MG, U87, GL15 were treated with 950 pM of Temozolomide; the lung cancer lines A549, HCC827, PC9 and breast MDA-MB-231 were treated with 20 pM, 0.008 pM, 0.020 pM and 20 pM of gefitinib respectively; Finally, the LnCAP prostate cancer line was treated with 1 nM Docetaxel. Statistical test: Kruskal-Wallis; Dunn's post-test, n = 2 or 3 independent experiments per line in triplicate. Lignée Inhb. Chim io (%) IC50 (pM) Inhib.Ma (%) C-Max (|iM) p-value Inhib.Min (%) C-Min (|iM) p-value Glioblastome U251 24h 1,79 65,09 + 55,74 33,04 10 0,0078 33,04 10 0,0078 48h 26,1 24,77 + 50,55 57,07 10 0,0076 57,07 10 0,0076 72h 41,7 > 100 80,07 10 0,0137 80,07 10 0,0137 8MG 24h 13,1 > 100 30,04 10 0,4253 30,04 10 0,4253 48h 60,4 > 100 68,55 10 0,9999 68,55 10 > 0,9999 72h 78,3 > 100 88,86 10 0,0108 88,86 10 0,0108 42MG 24h 5,27 29,36 + 17,68 30,16 10 0,5107 30,16 10 0,5107 48h 50,8 > 100 77,34 10 0,0063 77,34 10 0,0063 72h 76,2 > 100 90,84 10 0,0734 90,84 10 0,0734 U87 24h 1,97 > 100 15,5 10 0,8943 15,5 10 0,8943 48h 28,9 > 100 48,75 10 0,9999 48,75 10 > 0,9999 72h 80 > 100 84,42 10 0,9999 84,42 10 > 0,9999 GL15 24h 5.57 > 100 25.49 10 0.2317 25.49 10 0.2317 48h 58.2 > 100 59.5 10 0.9999 59.5 10 > 0.9999 72h 83.3 > 100 81.56 10 0.9999 81.56 10 > 0.9999 Pulmonary A549 24h 21.8 > 100 41.56 10 0.9999 41.56 10 > 0.9999 48h 34.9 > 100 56.32 10 0.9999 56.32 10 > 0.9999 72h 49.2 > 100 64.42 10 0.9999 64.42 10 > 0.9999 HCC827 24h 7.91 17.79 + 58.18 37.24 10 0.9999 37.24 10 > 0.9999 48h 1.82 13.69 + 2.79 43.08 10 0.1038 43.08 10 0.1038 72h 5.58 15.01 + 3.14 43.32 10 0.1609 43.32 10 0.1609 PC9 24h 14.8 12.89 + 5.60 54.29 10 0.0199 54.29 10 0.0199 48h 48.6 0.31 + 0.75 71.14 10 0.0469 71.14 10 0.0469 72h 76 > 100 89.8 10 0.0168 89.8 10 0.0168 Mammary MDA-MB-23 1 24h 32.3 > 100 52.13 10 0.9999 52.13 10 > 0.9999 48h 54.7 > 100 68.59 10 0.7865 68.59 10 0.7865 72h 68.9 > 100 79.08 10 0.9999 79.08 10 > 0.9999 Prostatic LnCAP 24h 2.02 8.04 + 0.9 55.96 10 0.4321 55.96 10 0.4321 48h 8.64 5.78 + 0.9 60.48 10 0.4321 60.48 10 0.4321 72h 23.3 4.51 + 2.58 67.67 10 0.5542 67.67 10 0.5542

[0224] Example 25: Influence of the sequence construct SEQ ID NO: 37 mimicking a FUT sequence binding FlnA on the viability of U251, 8MG, 42MG, U87 and GL15 glioblastoma cells in combination with standard therapies used in the clinic which is temozolomide (TMZ).

[0225] At tO 2xl03 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of the tested sequence construct SEQ ID NO: 37 from 105 M to 10 12 M. In addition, the glioblastoma lines U251, 8MG, 42MG, U87 and GL15 receive a treatment of 950 pM of temozolomide. The cell density is evaluated at 24h, 48h and 72h using the CellTiter-Glo 3D kit (Promega). The results are summarized in Table 25. The construct of sequence SEQ ID NO: 37 only shows significant additive effects to TMZ at 72h, 10 pM in the U251 line, bringing the effects of TMZ from 61.65% to 94.36% (p = 0.0066). Such effects are not reproduced in the other glioblastoma lines 8MG, 42MG, U87 and GL15 suggesting that the construct of sequence SEQ ID NO: 37 is not the most optimal for application in combination with TMZ in a patient's clinic.

[0226] Table 25 groups the experimental results relating to the effect of the construct SEQ ID NO 37 on the viability of different glioblastoma lines (U251, 8MG, 42MG, U87, GL15) in combination with the corresponding conventional therapy, temozolomide. The glioblastoma lines U251, 8MG, 42MG, U87, GL15 were treated with 950 pM Temozolomide. Statistical test: Kruskal-Wallis; Dunn post-test, n = 2 or 3 independent experiments per line in triplicate. Lignée Inhib. Chimi o(%) IC50 (pM) Inhib.Ma x(%) C-Max (|iM) p-value Inhib.Min (%) C-Min (|iM) p-value Glioblastome U251 24h 12,2 > 100 45,19 10 0,0031 45,19 10 0,0031 48h 40,5 2,23 + 7,24 59,25 10 0,2159 59,25 10 0,2159 72h 61,7 > 100 94,36 10 0,0066 94,36 10 0,0066 8MG 24h 12,8 > 100 18,07 10 0,9999 18,07 10 0,9999 48h 59,8 > 100 65,01 10 0,4051 65,01 10 0,4051 72h 76,8 > 100 74,43 10 0,9999 74,43 10 0,9999 42MG 24h 23,1 > 100 15,32 10 0,9999 15,32 10 0,9999 48h 62,4 > 100 58,38 10 0,9999 58,38 10 0,9999 72h 81,9 > 100 72,01 10 0,9999 72,01 10 0,9999 U87 24h 3,16 > 100 3,36 10 0,9999 3,36 10 0,9999 48h 61,7 > 100 53,26 10 0,9999 53,26 10 0,9999 72h 86,7 > 100 85,18 10 0,9999 85,18 10 0,9999 GL15 24h 4,65 > 100 -4,66 10 0,9999 -4,66 10 0,9999 48h 65,7 > 100 62,98 10 0,9999 62,98 10 0,9999 72h 86,5 > 100 87,73 10 0,9999 87,73 10 0,9999

[0228] Example 26: Influences the construction of sequence SEQ ID NO: 32 mimicking a sequence of FlnA binding UT on the viability of GB U251, 8MG, 42MG, U87 and GL15 cells in combination with the standard therapy used in the clinic which is temozolomide (TMZ).

[0229] At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of the construct of sequence SEQ ID NO: 32 tested from 105 M to 10 12 M. In addition, the GB lines U251, 8MG, 42MG, U87 and GL15 receive a treatment of 950 pM of TMZ. The cell density is evaluated at 24h, 48h and 72h using the CellTiter-Glo 3D kit (Promega). The results are grouped in Table 26. The construct of sequence SEQ ID NO: 32 does not show additive effects to TMZ in all the lines tested, suggesting that it is not suitable for application in combination with TMZ in the clinic in a patient. Table 26 groups the experimental results relating to the effect of the construct SEQ ID NO 32 on the viability of different glioblastoma lines (U251, 8MG, 42MG, U87, GL15) in combination with the corresponding conventional therapy, temo-zolomide.Glioblastoma lines U251, 8MG, 42MG, U87, GL15 were treated with 950 pM Temozolomide. Statistical test: Kruskal-Wallis; Dunn's post-test, n = 2 or 3 independent experiments per line in triplicate. Inhib lineage. Chem io (%) IC50 (pM) Inhib.Ma (%) Gmux (pM ) p-value Inhib.Min (%) GmIh (pM ) p-value Glioblastoma U251 24h -9.51 > 100 ND ND ND ND ND ND 48h 6.06 > 100 ND ND ND ND ND ND 72h 26.6 > 100 31.23 10 0.9999 31.23 10 > 0.9999 8MG 24h 12.8 > 100 3.45 10 0.0938 3.45 10 0.0938 48h 59.8 > 100 57.03 10 0.9999 57.03 10 > 0.9999 72h 76.8 > 100 71.71 10 0.3172 71.71 10 0.3172 42MG 24h 23.1 > 100 ND ND ND ND ND ND 48h 62.4 > 100 37.18 10 0.9999 37.18 10 > 0.9999 72h 81.9 > 100 67.03 10 0.9999 67.03 10 > 0.9999 U87 24h 3.16 > 100 ND ND 0.9999 ND ND > 0.9999 48h 61.7 > 100 34.1 10 0.0193 34.1 10 0.0193 72h 86.7 > 100 65.96 10 0.0228 65.96 10 0.0228 GL15 24h 4,65 > 100 ND ND ND ND ND ND 48h 65,7 > 100 35,42 10 0,0938 35,42 10 0,0938 72h 86,5 > 100 55,71 10 0,9999 55,71 10 > 0,9999

[0231] Example 27: Influence of the sequence construct SEQ ID NO: 30 mimicking a UT-binding FlnA sequence on the viability of GB U251, 8MG and 42MG cells in combination with the standard therapy used clinically which is temozolomide (TMZ). At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of the sequence construct SEQ ID NO: 30 tested from 105 M to 10 12 M. In addition, the GB U251, 8MG and 42MG lines receive a treatment of 950 pM of TMZ. The cell density is evaluated at 24h, 48h and 72h using the CellTiter-Glo 3D kit (Promega). The results are grouped in Table 27. The construct SEQ ID NO: 30 presents a significant additive effect to transient TMZ at 48h, at OpM, in the U251 line bringing its effect from 22.12% to 59.01% (p = 0.0193).This weak transient effect, not reproduced in the other two GB lines 8MG and 42MG, does not allow us to consider the construct of sequence SEQ ID NO: 30 as usable in combination with TMZ for a clinical application in a patient. Table 27 groups the experimental results relating to the effect of the construct SEQ ID NO: 30 on the viability of different glioblastoma lines (U251, 8MG and 42MG) in combination with the corresponding conventional therapy, temozolomide. The U251, 8MG and 42MG glioblastoma lines were treated with 950 pM of Temozolomide. Statistical test: Kruskal-Wallis; Dunn's post-test, n = 2 or 3 independent experiments per line in triplicate. Glioblastoma Lineage Inhibitor. Inhibition (%) IC50 (pM) Inhib.Max (%) Gmux (pM ) p-value Inhib.Min (%) CMi n (PM) p-value U251 24h 6.42 > 100 14.54 10 0.9999 14.54 10 > 0.9999 48h 22.1 0.28 59.01 10 0.0193 58.97 1 0.0438 72h 45.7 > 100 90.46 10 0.0697 90.46 10 0.0697 8MG 24h 3.45 > 100 2.07 10 0.9999 2.07 10 > 0.9999 48h 44 > 100 41,94 10 0,9999 41,94 10 > 0,9999 72h 85 > 100 79,83 10 0,9999 79,83 10 > 0,9999 42MG 24h 5,47 > 100 33,69 10 0,5126 33,69 10 0,5126 48h 49,3 > 100 45,11 10 0,9999 45,11 10 > 0,9999 72h 72,3 > 100 61,19 10 0,125 61,19 10 0,125

[0233] Example 28: Influence of the construct of sequence SEQ ID NO: 34 mimicking a FUT sequence binding FlnA on the viability of U251 glioblastoma cells in combination with the standard therapy used in clinic which is temozolomide (TMZ). At T0, 2x103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of construct SEQ ID NO: 34 tested from 105 M to 10 12 M. In addition, the GB U251 line receives a treatment of 950 pM of TMZ. The cell density is evaluated at 24h, 48h and 72h using the CellTiter-Glo 3D kit (Promega). The results are grouped in Table 28. The construct of sequence SEQ ID NO: 34, administered at 10 pM, presents significant additive inhibitory effects to TMZ in the GB U251 line, particularly significant at 72 hours, bringing the effect of TMZ alone from 55.82% to 83.33% (p = 0.0045). It is in fact approximately It is possible to use the construct with sequence SEQ ID NO: 34 in combination with TMZ in clinical practice on patients with GB of the same subgroup as the U251 line. Table 28 summarizes the experimental results relating to the effect of the construct SEQ ID NO: 34 on the viability of the U251 glioblastoma line (in combination with the corresponding conventional therapy, temozolomide). The U251 glioblastoma line was treated with 950 pM of Temozolomide. Statistical test: Kruskal-Wallis; Dunn's post-test, n = 2 or 3 independent experiments per line in triplicate.

[0234] [Tables28] Inhb lineage. Chem io (%) ic50 (pM ) InhibMax (%) Cmsx (pM ) p-value Inhib.Min (%) Cwin (pM ​​) p-value Glioblastoma U251 24h 7.78 3.79 + 5.97 49.98 10 0.008 44.42 1 0.0318 48h 24.7 100 61.09 10 0.1084 61.09 10 0.1084 72h 55.8 4.11 + 6.74 83.33 10 0.0045 82.59 1 0.0055

[0235] Example 29: Influence of the construction of sequence SEQ ID NO: 36 mimicking a FUT sequence binding FlnA on the viability of GB U251 cells in combination with the standard therapy used in the clinic which is temozolomide (TMZ).

[0236] At T0, 2 x 103 cells are seeded in the wells of a 96-well plate, in the presence of increasing concentrations of the construct of sequence SEQ ID NO: 36 tested from 105 M to 10 12 M. In addition, the GB U251 line receives a treatment of 950 pM of TMZ. The cell density is evaluated at 24 h, 48 h and 72 h using the CellTiter-Glo 3D kit (Promega). The results are grouped in Table 29. The construct of sequence SEQ ID NO: 36, administered at 10 pM, shows significant additive inhibitory effects to TMZ in the GB U251 line, particularly significant at 72 h, bringing the effect of TMZ alone from 69.77% to 95.83 (p = 0.0031). It is in fact conceivable to be able to use the sequence construct SEQ ID NO: 36 in combination with TMZ in the clinic on patients carrying the same GB subgroup as the U251 line. Table 29 groups together the relative experimental results to the effect of construct SEQ ID NO 36 on the viability of the glioblastoma line U251 (in combination with the corresponding conventional therapy, temozolomide. The glioblastoma line U251 was treated with 950 pM Temozolomide. Statistical test: Kruskal-Wallis; Dunn's post-test, n = 2 or 3 independent experiments per line in triplicate.

[0237] [Tables29] Inhb lineage. Chemo(%) ic50 (pM) Inhib.Max (%) Cmsx (pM) p-value Inhib.Min (%) Cyim (pM) p-value Glioblastoma U251 24h 20 > 100 25.65 10 0.9999 25.65 10 0.9999 48h 40.5 11.18 + 37.59 69.99 10 0.9999 69.99 10 0.9999 72h 69.8 > 100 95.83 10 0.0031 93.04 1 0.0193

Claims

Claims

1. A construct comprising a cell-penetrating peptide sequence coupled by a peptide bond to at least one first linker molecule, which is coupled by a peptide bond to the N-terminus of an interfering amino acid sequence selected from: a) sequences comprising or consisting of the following sequence: VTYCPTEPGNYIINIKFADQHVPGSPFSVKVTGEGRVKESITRRRR APSVANVGSHCDLSLKIPEISIQDMTAQVTSPSGKTHEAEIVEGE NHTYCIRFVPAE (SEQ ID NO: 1 or FlnA 2104-2206) which forms domain 2104-2206 of the human FlnA protein;b) sequences comprising or consisting of a fragment of the sequence SEQ ID NO: 1 and capable of associating with the sequence VRGPGSGGGRGPVPSLQPRAR (SEQ ID NO: 2 or UT-330-350) which defines domain 330-350 of the UT receptor or with a fragment of this sequence SEQ ID NO: 2, in particular with the fragment of sequence GGGRGPVPSLQPRAR (SEQ ID NO: 3 or UT-336-350) forming domain 336-350 of the UT receptor or with the fragment RGPVPSLQPRAR (SEQ ID NO: 4 or UT-339-350) defining domain 339-350 of the UT receptor; c) sequences comprising or consisting of a fragment of the sequence SEQ ID NO: 2, in particular the fragment forming domain 330-350 of the UT receptor (SEQ ID NO: 2) or the fragment forming domain 336-350 of the UT receptor (SEQ ID NO: 3) or the fragment forming domain 339-350 of the UT receptor (SEQ ID NO: 4) and capable of associating with a fragment of the sequence SEQ ID NO: 1;(d) sequences having at least 90% identity and preferably at least 95% identity with the sequences defined in subparagraphs (a) to (c); and (a) sequences substantially homologous to the sequences defined in subparagraphs (a) to (d) and preferably derived from the latter by one or more conservative substitutions.;

2. Construction according to claim 1, characterized in that said at least one first binding molecule is an amino acid, optionally modified and in particular a beta-alanine molecule.

3. Construction according to claim 1 or 2, characterized in that said interfering amino acid sequence is chosen from the amino acid sequences defined in paragraph b) and in particular from the following interfering sequences: - MTAQVTSPSGKTHEAEIVE (SEQ ID NO: 5 or FlnA-D20-CD), GNYIINIKFADQHVPGSPFSVKVT (SEQ ID NO: 6 or FlnA-D19-FG), THEAEIVEGENHTYCIRF (SEQ ID NO: 7 or FlnA-D20-DE); - peptide sequences having at least 90% and preferably at least 95% identity with said sequences and substantially homologous sequences, preferably deriving from the sequences SEQ ID NO: 5, SEQ ID NO: 6 or SEQ ID NO: 7 by one or more conservative substitutions. - RGPVPSLQPRAR (SEQ ID NO: 4 or UT-339-350) and GG-GRGPVPSLQPRAR (SEQ ID NO: 3 or UT-336-350) and the peptide sequences having at least 90% and preferably at least 95% identity with said sequences SEQ ID NO: 3 and SEQ ID NO: 4 and the substantially homologous sequences, preferably deriving from the sequences SEQ ID NO: 3 or SEQ ID NO: 4 by one or more conservative substitutions.

4. Construction according to any one of the preceding claims, characterized in that said cell penetration sequence is chosen from the following sequences: -TCTWLKYH (SEQ ID NO: 8 or Glio) and the peptide sequences having at least 90% and preferably at least 95% identity with said sequence SEQ ID NO: 8 and the substantially homologous sequences, preferably deriving from the sequence SEQ ID NO: 8 by one or more conservative substitutions; - the peptide sequence GRRRQRRKKRKCCKRKKRRQRRRG (SEQ ID NO: 9 or CycloGlio) in which residues 12 and 13 (cysteine) are linked by a disulfide bridge and in which residues 2 to 10 and 15 to 23 are dextrorotatory (D) amino acids and the peptide sequences having at least 90% and preferably at least 95% identity with said sequence SEQ ID NO: 9 and the substantially homologous sequences, preferably deriving from the sequence SEQ ID NO: 9 by one or more conservative substitutions, the two ends of said penetration sequence being each linked by a peptide bond to a first linker molecule which is a amino acid, possibly modified, said linking molecule itself being linked by a peptide bond to an interfering sequence, the two interfering sequences being identical or different.

5. Construction according to claim 4, characterized in that said cell penetration sequence is chosen from the peptide sequence GRRRQRRKKRKCCKRKKRRQRRRG (SEQ ID NO: 9 or CycloGlio) in which residues 12 and 13 (cysteine) are linked by a disulfide bridge and in which residues 2 to 10 and 15 to 23 are dextrorotatory (D) amino acids and the peptide sequences having at least 90% and preferably at least 95% identity with said sequence SEQ ID NO: 9 and the substantially homologous sequences, preferably deriving from the sequence SEQ ID NO: 9 by one or more conservative substitutions, in that the first two linker molecules are identical and in particular beta alanine molecules;and in that -one of the interfering sequences is chosen from the sequences defined in paragraphs a) and b) of claim 1, in particular from the following interfering sequences: MTAQVTSPSGKTHEAEIVE (SEQ ID NO: 5 or FlnA-D20-CD), GNYIINIKFADQHVPGSPFSVKVT (SEQ ID NO: 6 or FlnA-D19-FG), THEAEIVEGENHTYCIRF (SEQ ID NO: 7 or FlnA-D20-DE) and the peptide sequences having at least 90% and preferably at least 95% identity with said sequences and the substantially homologous sequences, preferably deriving from the sequences SEQ ID NO: 5, SEQ ID NO: 6 or SEQ ID NO: 7 by one or more conservative substitutions;and - the other interfering sequence is chosen from the sequences defined in paragraph c) of claim 1 and in particular from the following interfering sequences: RGPVPSLQPRAR (SEQ ID NO: 4 or UT-339-350) and GGGRGPVPSLQPRAR (SEQ ID NO: 3 or UT-336-350) and the peptide sequences having at least 90% and preferably at least 95% identity with said sequences SEQ ID NO: 3 and SEQ ID NO: 4 and the substantially homologous sequences, preferably deriving from the sequences SEQ ID NO: 3 or SEQ ID NO: 4 by one or more conservative substitutions.;

6. Interfering construct according to any one of claims 4 and 5, characterized in that said cell penetration sequence is chosen from the peptide sequence GRRRQRRKKRKCCKRK- KRRQRRRG (SEQ ID NO: 9 or CycloGlio) in which residues 12 and 13 (cysteine) are linked by a disulfide bridge and in which residues 2 to 10 and 15 to 23 are dextrorotatory (D) amino acids and the peptide sequences having at least 90% and preferably at least 95% identity with said sequence SEQ ID NO: 9 and the substantially homologous sequences, preferably deriving from the sequence SEQ ID NO: 9 by one or more conservative substitutions, the lysines at positions 11 and 14 of said cell penetrating sequence are acetylated.

7. Interfering construct according to any one of the preceding claims, characterized in that it is chosen from the following sequence constructs: TVKVSFPSGPVHQDAFKINIIYNGXGrrrqrrkkrKCCKrkkrrqrrrGXG NYIINIKFADQHVPGSPFSVKVT (SEQ ID NO: 10, also called FlnA-CPPD19-FG-CycloGlio) in which residues 37 and 38 are linked by a disulfide bridge, X is in both positions an optionally modified amino acid and preferably beta-alanine in both positions and residues 27 to 35 and 40 to 48 are dextrorotatory (D) amino acids and in which the lysines in positions 36 and 39 are acetylated; EVIEAEHTKGSPSTVQATMXGrrrqrrkkrKCCKrkkrrqrrrGXMTAQV TSPSGKTHEAEIVE (SEQ ID NO: 11; also referred to as FlnA-CPPD20-CD-CycloGlio) wherein residues 32 and 33 are linked by a disulfide bridge, X is an optionally modified amino acid and preferably beta-alanine in both positions and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids and wherein the lysines at positions 31 and 34 are acetylated; FRISYTHNEGEVIEAEHTXGrrrqrrkkrKCCKrkkrrqrrrGXTHEAEIVE GENHTYSIRF (SEQ ID NO: 12; also referred to as FlnA-CPPD20-DE-CycloGlio) wherein residues 31 and 32 are linked by a disulfide bridge, X is an optionally modified amino acid and preferably beta-alanine and residues 21 to 29 and 34 to 42 are dextrorotatory (D) amino acids and wherein the lysines at positions 30 and 33 are acetylated; TCTWLKYHXGNYIINIKFADQHVPGSPFSVKVT (SEQ ID NO: 13; also referred to as FlnA-CPPD19-FG-Glio) wherein X is an optionally modified amino acid and preferably beta-alanine; TCTWLKYHXMTAQVTSPSGKTHEAEIVE (SEQ ID NO: 14; also referred to as FlnA-CPPD20-CD-Glio) in which X is an optionally modified amino acid and preferably beta-alanine; TCTWLKYHXTHEAEIVEGENHTYCIRF (SEQ ID NO: 15; also referred to as FlnA-CPPD20-DE-Glio) in which X is an optionally modified amino acid and preferably beta-alanine; RARPQLSPVPGRGGGXGrrrqrrkkrKCCKrkkrrqrrrGXGGGRGPVPSL QPRAR (SEQ ID NO: 16, also referred to as UT-CPP336-350-CycloGlio) wherein residues 28 and 29 are linked by a disulfide bridge, X is an optionally modified amino acid and preferably beta-alanine in both positions and residues 18 to 26 and 31 to 39 are dextrorotatory (D) amino acids and wherein the lysines at positions 27 and 30 are acetylated; RARPQLSPVPGRXGrrrqrrkkrKCCKrkkrrqrrrGXRGPVPSLQPRAR SEQ ID NO: 17; also referred to as UT-CPP339-350-CycloGlio) wherein residues 25 and 26 are disulfide bonded, X is an optionally modified amino acid and preferably beta-alanine in both positions and residues 15 to 23 and 28 to 36 are dextrorotatory (D) amino acids and wherein lysines at positions 24 and 27 are acetylated, TCTWLKYHXGGGRGPVPSLQPRAR (SEQ ID NO: 18; also referred to as UT-CPP336-350-Glio) wherein X is an optionally modified amino acid and preferably beta-alanine; - TCTWLKYHXRGPVPSLQPRAR (SEQ ID NO: 19; also referred to as UT-CPP339-350-Glio) in which X is an optionally modified amino acid and preferably beta-alanine; - constructs exhibiting at least 90% identity and preferably at least 95% identity with the aforementioned constructs; and - constructs which are substantially homologous and preferably derived from the sequences SEQ ID NO: 10 to SEQ ID NO: 19 by one or more conservative substitutions.

8. Construct according to any one of the preceding claims, characterized in that it is chosen from the following sequence constructs: TVKVSFPSGPVHQDAFKINIIYNGAGrrrqrrkkrKCCKrkkrrqrrrGAG NYIINIKFADQHVPGSPFSVKVT(SEQ ID NO: 28, also called FlnA-CPPD19-FG-CycloGlio-syn) in which residues 37 and 38 are linked by a disulfide bridge, the alanines in positions 25 and 50 are beta-alanine and residues 27 to 35 and 40 to 48 are acids dextrorotatory (D) amino acids and in which the lysines at positions 36 and 39 are acetylated; EVIEAEHTKGSPSTVQATMAGrrrqrrkkrKCCKrkkrrqrrrGAMTAQV TSPSGKTHEAEIVE (SEQ ID NO: 29; also referred to as FlnA-CPPD20-CD-CycloGlio-syn) wherein residues 32 and 33 are disulfide bonded, alanines at positions 20 and 45 are beta-alanine and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids and wherein lysines at positions 31 and 34 are acetylated; FRISYTHNEGEVIEAEHTAGrrrqrrkkrKCCKrkkrrqrrrGATHEAEIVE GENHTYSIRF (SEQ ID NO: 30; also referred to as FlnA-CPPD20-DE-CycloGlio-syn) wherein residues 31 and 32 are disulfide bonded, alanines at positions 19 and 44 are beta-alanine, and residues 21 to 29 and 34 to 42 are dextrorotatory (D) amino acids, and wherein lysines at positions 30 and 33 are acetylated; TCTWLKYHAGNYIINIKFADQHVPGSPFSVKVT (SEQ ID NO: 31; also referred to as FlnA-CPPD19-FG-Glio-syn) wherein the alanine at position 9 is a beta-alanine; TCTWLKYHAMTAQVTSPSGKTHEAEIVE (SEQ ID NO: 32; also referred to as FlnA-CPPD20-CD-Glio-syn) wherein the alanine at position 9 is a beta-alanine; TCTWLKYHATHEAEIVEGENHTYCIRF (SEQ ID NO: 33; also referred to as FlnA-CPPD20-DE-Glio-syn) wherein the alanine at position 9 is a beta-alanine; RARPQLSPVPGRGGGAGrrrqrrkkrKCCKrkkrrqrrrGAGGGRGPVPSL QPRAR (SEQ ID NO: 34; also referred to as UT-CPP336-350-CycloGlio-syn) wherein residues 28 and 29 are disulfide bonded, alanines at positions 16 and 41 are beta-alanine, residues 18 to 26 and 31 to 39 are dextrorotatory (D) amino acids and wherein lysines at positions 27 and 30 are acetylated; RARPQLSPVPGRAGrrrqrrkkrKCCKrkkrrqrrrGARGPVPSLQPRAR SEQ ID NO: 35; also referred to as UT-CPP339-350-CycloGlio-syn) wherein residues 25 and 26 are disulfide bonded, alanines at positions 13 and 38 are beta-alanine and residues 15 to 23 and 28 to 36 are dextrorotatory (D) amino acids and wherein lysines at positions 24 and 27 are

9.

10. acetylated; TCTWLKYHAGGGRGPVPSLQPRAR (SEQ ID NO: 36; also referred to as UT-CPP336-350-Glio-syn) wherein the alanine at position 9 is a beta-alanine; TCTWLKYHARGPVPSLQPRAR (SEQ ID NO: 37; also referred to as UT-CPP339-350-Glio-syn) wherein the alanine at position 9 is a beta-alanine; the sequences having at least 90% identity and, preferably, at least 95% identity with the aforementioned sequences and the sequences substantially homologous to the aforementioned sequences and preferably deriving from the latter by one or more conservative substitutions. Construction according to any one of claims 1 to 5 characterized in that it further comprises a marking agent capable of penetrating into the cell. Construct according to claim 9, characterized in that it is chosen from the following sequence constructs: TVKVSFPSGPVHQDAFKINIIYNGAGrrrqrrkkrKCCKrkkrrqrrrGAG NYIINIKFADQHVPGSPFSVKVT(SEQ ID: 38, also called Mq-FlnA-CPPD19-FG-CycloGlio-syn) in which residues 37 and 38 are linked by a disulfide bridge, the alanines in positions 25 and 50 are beta-alanine and residues 27 to 35 and 40 to 48 are dextrorotatory (D) amino acids and residues 36 and 39 are each linked by a peptide bond to the carboxylic acid group of 5-carboxytetramethylrhodamine; EVIEAEHTKGSPSTVQATMAGrrrqrrkkrKCCKrkkrrqrrrGAMTAQV TSPSGKTHEAEIVE (SEQ ID NO: 39; also referred to as Mq-FlnA-CPPD20-CD-CycloGlio-syn) wherein residues 32 and 33 are linked by a disulfide bridge, the alanines at positions 20 and 45 are beta-alanine and residues 22 to 30 and 35 to 43 are dextrorotatory (D) amino acids and residues 31 and 34 are each linked by a peptide bond to the carboxylic acid group of 5-carboxytetramethylrhodamine; FRISYTHNEGEVIEAEHTAGrrrqrrkkrKCCKrkkrrqrrrGATHEAEIVE GENHTYSIRF (SEQ ID NO: 40; also referred to as Mq-FlnA-CPPD20-DE-CycloGlio-syn) wherein residues 31 and 32 are disulfide bonded, alanines at positions 19 and 44 are beta-alanine and residues 21 to 29 and 34 to 42 are dextrorotatory (D) amino acids and residues 30 and 33 are each disulfide bonded peptide to the carboxylic acid group of 5-carboxytetramethylrhodamine; ATCTWLKYHAGNYIINIKFADQHVPGSPFSVKVT (SEQ ID NO: 41; also referred to as Mq-FlnA-CPPD19-FG-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid; ATCTWLKYHAMTAQVTSPSGKTHEAEIVE (SEQ ID NO: 42; also referred to as Mq-FlnA-CPPD20-CD-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid; ATCTWLKYHATHEAEIVEGENHTYCIRF (SEQ ID NO: 43; also referred to as Mq-FlnA-CPPD20-DE-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid; RARPQLSPVPGRGGGAGrrrqrrkkrKCCKrkkrrqrrrGAGGGRGPVPSL QPRAR (SEQ ID NO: 44; also referred to as Mq- UT-CPP336-350-CycloGlio-syn) in which residues 28 and 29 are linked by a disulfide bridge, the alanines at positions 16 and 41 are beta-alanine and residues 18 to 26 and 31 to 39 are dextrorotatory (D) amino acids and residues 27 and 30 are each linked by a peptide bond to the carboxylic acid group of 5-carboxytetramethylrhodamine; RARPQLSPVPGRAGrrrqrrkkrKCCKrkkrrqrrrGARGPVPSLQPRAR SEQ ID NO: 45; also called Mq- UT-CPP339-350-CycloGlio-syn) wherein residues 25 and 26 are linked by a disulfide bridge, the alanines at positions 13 and 38 are beta-alanine and residues 15 to 23 and 28 to 36 are dextrorotatory (D) amino acids residues 24 and 27 are each linked by a peptide bond to the carboxylic acid group of 5-carboxytetramethylrhodamine, ATCTWLKYHAGGGRGPVPSLQPRAR (SEQ ID NO: 46; also referred to as Mq-UT-CPP336-350-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid; ATCTWLKYHARGPVPSLQPRAR (SEQ ID NO: 47; also referred to as Mq-UT-CPP339-350-Glio-syn) wherein the alanine at position 1 and the alanine at position 10 are beta-alanine and wherein the alanine at position 1 is linked by a peptide bond to the carboxylic acid group of 7-diethylaminocoumarin-3-carboxylic acid; - sequences having at least 90% identity and, preferably, at least 95% identity with the aforementioned sequences and sequences substantially homologous to the aforementioned sequences and preferably deriving from the latter by one or more conservative substitutions.

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